AU2004230926A1

AU2004230926A1 - CGRP receptor antagonists

Info

Publication number: AU2004230926A1
Application number: AU2004230926A
Authority: AU
Inventors: Christopher S. Burgey; Zhengwu J. Deng; Diem N. Nguyen; Daniel V. Paone; Anthony W. Shaw; Theresa M. Williams
Original assignee: Merck and Co Inc
Current assignee: Merck Sharp and Dohme LLC
Priority date: 2003-04-15
Filing date: 2004-04-09
Publication date: 2004-10-28
Anticipated expiration: 2024-04-09
Also published as: EP2039694B1; US20050256098A1; CO5640130A2; US7534784B2; US20070225272A1; NO327655B1; RU2308458C2; PT1638969E; DK1638969T3; US20080280857A1; WO2004092166A3; HRP20080666T3; US20040229861A1; MA27728A1; DE602004017608D1; IS2759B; NZ543357A; US6953790B2; US7772224B2; AR045887A1

Description

WO 2004/092166 PCT/US2004/010851 TITLE OF THE INVENTION CGRP RECEPTOR ANTAGONISTS BACKGROUND OF THE INVENTION 5 CGRP (Calcitonin Gene-Related Peptide) is a naturally occurring 37-amino acid peptide that is generated by tissue-specific alternate processing of calcitonin messenger RNA and is widely distributed in the central and peripheral nervous system. CGRP is localized predominantly in sensory afferent and central neurons and mediates several biological actions, including vasodilation. CGRP is expressed in alpha- and beta-forms that vary by one and three 10 amino acids in the rat and human, respectively. CGRP-alpha and CGRP-beta display similar biological properties. When released from the cell, CGRP initiates its biological responses by binding to specific cell surface receptors that are predominantly coupled to the activation of adenylyl cyclase. CGRP receptors have been identified and pharmacologically evaluated in several tissues and cells, including those of brain, cardiovascular, endothelial, and smooth 15 muscle origin. CGRP is a potent vasodilator that has been implicated in the pathology of cerebrovascular disorders such as migraine and cluster headache. In clinical studies, elevated levels of CGRP in the jugular vein were found to occur during migraine attacks (Goadsby et al., Ann. Neurol., 1990, 28, 183-187). CGRP activates receptors on the smooth muscle of 20 intracranial vessels, leading to increased vasodilation, which is thought to be the major source of headache pain during migraine attacks (Lance, Headache Pathogenesis: Monoamines, Neuropeptides, Purines and Nitric Oxide, Lippincott-Raven Publishers, 1997, 3-9). The middle meningeal artery, the principle artery in the dura mater, is innervated by sensory fibers from the trigeminal ganglion which contain several neuropeptides, including CGRP. Trigeminal ganglion 25 stimulation in the cat resulted in increased levels of CGRP, and in humans, activation of the trigeminal system caused facial flushing and increased levels of CGRP in the external jugular vein (Goadsby et al., Ann. Neurol., 1988, 23, 193-196). Electrical stimulation of the dura mater in rats increased the diameter of the middle meningeal artery, an effect that was blocked by prior administration of CGRP(8-37), a peptide CGRP antagonist (Williamson et al., Cephalalgia, 30 1997, 17, 525-531). Trigeminal ganglion stimulation increased facial blood flow in the rat, which was inhibited by CGRP(8-37) (Escott et al., Brain Res. 1995, 669, 93-99). Electrical stimulation of the trigeminal ganglion in marmoset produced an increase in facial blood flow that could be blocked by the non-peptide CGRP antagonist BIBN4096BS (Doods et al., Br. J. Pharmacol., 2000, 129, 420-423). Thus the vascular effects of CGRP may be attenuated, prevented or - 1 - WO 2004/092166 PCT/US2004/010851 reversed by a CGRP antagonist. In recently reported clinical trials, the CGRP receptor antagonist BIiBN 4096 BS was reported to be effective in treating acute attacks of migraine (Olesen et al., N. Engl. J. Med. 2004, 350:1104-1110). CGRP-mediated vasodilation of rat middle meningeal artery was shown to 5 sensitize neurons of the trigeminal nucleus caudalis (Williamson et al., The CGRP Family: Calcitonin Gene-Related Peptide (CGRP), Amylin, and Adrenomedullin, Landes Bioscience, 2000, 245-247). Similarly, distention of dural blood vessels during migraine headache may sensitize trigeminal neurons. Some of the associated symptoms of migraine, including extra cranial pain and facial allodynia, may be the result of sensitized trigeminal neurons (Burstein et 10 al., Ann. Neurol. 2000, 47, 614-624). A CGRP antagonist may be beneficial in attenuating, preventing or reversing the effects of neuronal sensitization. The ability of the compounds of the present invention to act as CGRP antagonists makes them useful pharmacological agents for disorders that involve CGRP in humans and animals, but particularly in humans. Such disorders include migraine and cluster headache 15 (Doods, Curr Opin Inves Drugs, 2001, 2 (9), 1261-1268; Edvinsson et al., Cephalalgia, 1994, 14, 320-327); chronic tension type headache (Ashina et al., Neurology, 2000, 14, 1335-1340); pain (Yu et al., Eur. J. Pharm., 1998, 347, 275-282); chronic pain (Hulsebosch et al., Pain, 2000, 86, 163-175); neurogenic inflammation and inflammatory pain (Holzer, Neurosci., 1988, 24, 739 768; Delay-Goyet et al., Acta Physiol. Scanda. 1992, 146, 537-538; Salmon et al., Nature 20 Neurosci., 2001, 4(4), 357-358); eye pain (May et al. Cephalalgia, 2002, 22, 195-196), tooth pain (Awawdeh et al., Int. Endocrin. J., 2002, 35, 30-36), non-insulin dependent diabetes mellitus (Molina et al., Diabetes, 1990, 39, 260-265); vascular disorders; inflammation (Zhang et al., Pain, 2001, 89, 265), arthritis, bronchial hyperreactivity, asthma, (Foster et al., Ann. NY Acad. Sci., 1992, 657, 397-404; Schini et al., Am. J. Physiol., 1994, 267, H2483-H2490; Zheng et al., J. 25 Virol., 1993, 67, 5786-5791); shock, sepsis (Beer et al., Crit. Care Med., 2002, 30 (8), 1794 1798); opiate withdrawal syndrome (Salmon et al., Nature Neurosci., 2001, 4(4), 357-358) morphine tolerance (Menard et al., J. Neurosci., 1996, 16 (7), 2342-2351); hot flashes in men and women (Chen et al., Lancet, 1993, 342, 49; Spetz et al., J. Urology, 2001, 166, 1720-1723); allergic dermatitis (Wallengren, Contact Dermatitis, 2000, 43 (3), 137-143); psoriasis; 30 encephalitis, brain trauma, ischaemia, stroke, epilepsy, and neurodegenerative diseases (Rohrenbeck et al., Neurobiol. of Disease 1999, 6, 15-34); skin diseases (Geppetti and Holzer, Eds., Neurogenic Inflammation, 1996, CRC Press, Boca Raton, FL), neurogenic cutaneous redness, skin rosaceousness and erythema; tinnitus (Herzog et al., J. Membrane Biology, 2002, 189(3), 225); inflammatory bowel disease, irritable bowel syndrome, (Hoffman et al. -2- WO 2004/092166 PCT/US2004/010851 Scandinavian Journal of Gastroenterology, 2002, 37(4) 414-422) and cystitis. Of particular importance is the acute or prophylactic treatment of headache, including migraine and cluster headache. The present invention relates to compounds that are useful as ligands for CGRP 5 receptors, in particular antagonists for CGRP receptors, processes for their preparation, their use in therapy, pharmaceutical compositions comprising them and methods of therapy using them. SUMMARY OF THE INVENTION 10 The present invention is directed to compounds of Formula I: R1 Q" U R2 0 (R)_ W- N G NH R 4 11B y

R

2 R and Formula II: 15 R1 Q,5-T U B N 2 B RW G NH RB y 0 II (where variables R1, R 2 , R 3 , R 4 , A, B, G, J, Q, T, U, V, W, X and Y are as defined herein) useful as antagonists of CGRP receptors and useful in the treatment or prevention of diseases in 20 which the CGRP is involved, such as headache, migraine and cluster headache. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which CGRP is involved. 25 -3- WO 2004/092166 PCT/US2004/010851 DETAILED DESCRIPTION OF THE INVENTION The present invention is directed to CGRP antagonists which include compounds of Formula I: R1 Q U R2 \ 0 ( 3)19 R2 N 9 -jl r 2A W- N G NH 5 R 0 wherein: A is a bond, C(R 2 )2, 0, S(O)m or NR 2 ; 10 B is (C(R 2 )2)n; R is selected from: 15 1) H, C 1

-C

6 alkyl, C 2

-C

6 alkenyl, C 2

-C

6 alkynyl, C3-6 cycloalkyl, and heterocycle, unsubstituted or substituted with one or more substituents independently selected from: a) C1-6 alkyl, 20 b) C3-6 cycloalkyl, c) aryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , d) heteroaryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , 25 e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , f) (F)pC1-3 alkyl, g) halogen, h) OR 4 30 i) O(CH2)s OR 4 , -4- WO 2004/092166 PCT/US2004/010851 j) C0 2

R

4 , k) (CO)NR' 0 RII, 1) O(CO)NR 1 0

R

1 I, m) N(R 4

)(CO)NR

10

R

1 1, 5 n) N(RIO)(CO)R 1 1, o) N(RIO)(CO)OR 1 1, p) S02NR 10

R

1 I, q) N(R1 0 ) SO2R11, r) S(O)mR 10 , 10 s) CN, t) NRIORRi, u) N(R 10

)(CO)NR

4 R 11 , and, v) O(CO)R 4 ; 15 2) aryl or heteroaryl, unsubstituted or substituted with one or more substituents independently selected from: a) C1-6 alkyl, b) C3-6 cycloalkyl, c) aryl, unsubstituted or substituted with 1-5 substituents where 20 the substituents are independently selected from R 4 , d) heteroaryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , 25 f) (F)pC1-3 alkyl, g) halogen, h) OR 4 , i) O(CH2)sOR 4 , 30 j) C0 2

R

4 , k) (CO)NROR'I, 1) O(CO)NR 1 0 RIl, m) N(R 4

)(CO)NR

10 RIl, n) N(R 10 )(CO)RIl, -5- WO 2004/092166 PCT/US2004/010851 o) N(R1O)(CO)0R 1 1, p) SO2NR1 0 RII, q) N(R 10 ) S02R 1 1 , r) S(O)mR1 0 , 5 s) CN, t)

NR

1 0 Ril, u) N(R 10

)(CO)NR

4 RII, and v) O(CO)R 4 ; 2 10 R is independently selected from: 1) H, C 0

-C

6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C3-6 cycloalkyl and heterocycle, unsubstituted or substituted with one or more substituents independently selected from: 15 a) Cp6alkyl, b) C3-6 cycloalkyl, c) aryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , d) heteroaryl, unsubstituted or substituted with 1-5 substituents 20 where the substituents are independently selected from R 4 , e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , f) (F)pCL-3 alkyl, 25 g) halogen, h) OR 4 , i) O(CH2)sOR 4 , j) C0 2

R

4 , k) (CO)NR' 0

R

1 1 , 30 1) O(CO)NR1 0 R 1, m) N(R 4 )(CO)NRIORIl, n) N(R 1 0 )(CO)R11, o) N(R 10 )(CO)ORI I, p) SO2NR1 0 RIl, -6- WO 2004/092166 PCT/US2004/010851 q) N(R1 0 )S02RI1, r) S(O)mR 10 , s) CN, t) NRI1Ril, 5 u) N(R 1 0

)(CO)NR

4 R 1 1 , and, v) O(CO)R 4 ; 2) aryl or heteroaryl, unsubstituted or substituted with one or more substituents independently selected from: 10 a) C1-6 alkyl, b) C3-6 cycloalkyl, c) aryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , d) heteroaryl, unsubstituted or substituted with 1-5 substituents 15 where the substituents are independently selected from R 4 , e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , f) (F)pC1-3 alkyl, g) halogen, 20 h) OR 4 , i) O(CH2)sOR 4 , j) C0 2

R

4 , k) (CO)NR 1 ORi, 1) O(CO)NRIOR 1 1 , 25 m) N(R 4

)(CO)NR

10 RII, n) N(R10)(CO)Ril1, o) N(R 10

)(CO)OR

1 1, p) SO2NR1 0 R"1. q) N(R1 0 ) SO2R' 1, 30 r) S(O)mR1 0 , s) CN, t) NRIORil, u) N(RI0)(CO)NR 4

R

1 1 , and v) O(CO)R 4 , -7- WO 2004/092166 PCT/US2004/010851 or, any two independent R 2 on the same or adjacent atoms may be joined together to form a ring selected from cyclobutyl, cyclopentenyl, cyclopentyl, cyclohexenyl, cyclohexyl, phenyl, naphthyl, thienyl, thiazolyl, thiazolinyl, oxazolyl, oxazolinyl, imidazolyl, 5 imidazolinyl, imidazolidinyl, pyridyl, pyrimidyl, pyrazinyl, pyrrolyl, pyrrolinyl, morpholinyl, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S-dioxide, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridyl, furanyl, dihydrofuranyl, dihydropyranyl and piperazinyl; 10 RIO and R I I are independently selected from: H, Cl-6 alkyl, (F)pC-6 alkyl, C3-6 cycloalkyl, aryl, heteroaryl, and benzyl, unsubstituted or substituted with halogen, hydroxy or C 1

-C

6 alkoxy, where R10 and R Il may be joined together to form a ring selected from: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 ; 15

R

4 is independently selected from: H, C1-6 alkyl, (F)pCI-6 alkyl, C3-6 cycloalkyl, aryl, heteroaryl and benzyl, unsubstituted or substituted with halogen, hydroxy or Cl-C6 alkoxy; W is 0, NR 4 or C(R 4 )2; 20 X is C or S; Y is 0, (R 4 )2, NCN, NSO2CH3, NCONH2, or Y is 02 when X is S; 25 R 6 is independently selected from H and: a) Cl-6 alkyl, b) C3-6 cycloalkyl, c) aryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , 30 d) heteroaryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , f) (F)pCl-3 alkyl, -8- WO 2004/092166 PCT/US2004/010851 g) halogen, h) OR 4 , i) O(CH2)sOR', j) CO 2 R4, 5 k) (CO)NR 10 RII, 1) O(CO)NR 10

R'

1 , m) N(R 4 )(CO)NR1 0 RII, n) N(R 1

O)(CO)RI

1 , o) N(R1O)(CO)OR 1 1, 10 p) SO2NR1 0

R'

1 , q) N(RIO) SO2RI 1, r) S(O)mR 10 , s) CN, t) NR 1 0 Rll, 15 u) N(R 1

O)(CO)NR

4 R I 1 , and v) O(CO)R 4 ; G-J is selected from: N, N-C(R 5 )2, C=C(R 5 ), C=N; C(R 5 ), C(R5)-C(R 5 )2, C(R 5

)-C(R

5 )2

C(R

5 )2, C=C(R 5

)-C(R

5 )2, C(R5)-C(R 5

)=C(R

5 ), C(R5)-C(R 5 )2-N(R 5 ), C=C(R 5

)-N(R

5 ), 20 C(R 5

)-C(R

5 )=N, C(R5)-N(R 5

)-C(R

5 )2, C=N-C(R 5 )2, C(R5)-N=C(R 5 ), C(R5)-N(R 5

)-N(R

5 ),

C-N-N(R

5 ), N-C(R 5 )2-C(R 5 )2, N-C(R 5

)=C(R

5 ), N-C(R5)2-N(R 5 ), N-C(R 5 )=N, N-N(R 5

)

C(R

5 )2 and N-N=C(R 5 ); Q, T, U and V are each independently a carbon atom or a nitrogen atom wherein at least one but 25 no more than three of Q, T, U and V are nitrogen atoms, of which one may be optionally an N oxide, and wherein when any of Q, T, U, or V is a carbon atom it is unsubstituted or substituted where the substituents are independently selected from R 6 ;

R

5 is independently selected from H, substituted or unsubstituted C1-C3 alkyl, CN, OR 4 , 30 N(R 4 )2 and C0 2

R

4 ;

R

3 is independently selected from H, substituted or unsubstituted C1-C3 alkyl, F, CN and C0 2

R

4 ; -9- WO 2004/092166 PCT/US2004/010851 p is 0 to 2q+1, for a substituent with q carbons; m is 0, 1 or 2; n is 0 or 1; 5 s is 1, 2 or 3; and pharmaceutically acceptable salts and individual diastereomers thereof. Further embodiments of the invention are CGRP antagonists of Formula I which 10 include compounds of the Formula Ia:

R

1 Q -U R2\ 0 (R') 1

-

9 N RW N G H 2 R 4 y la 15 wherein: A is a bond, C(R 2 )2, 0, S(O)m or NR 2 ; B is (C(R 2 )2)n; Y is 0 or NCN; and n is 0 or 1; and 20 RI, R 2 , R 4 , W, Y, R 3 , G-J, Q, T, U, V and m are as defined in Formula I; and pharmaceutically acceptable salts and individual stereoisomers thereof. Still further embodiments of the invention are CGRP antagonists of Formula I which include compounds of the Formula Ib: 25 R' Q 'U 02 (R 3

)

19 g R2 r R4W N G NH R 0 0 - 10- WO 2004/092166 PCT/US2004/010851 Ib wherein: A is a bond, C(R 2 )2, 0, S(O)m or NR 2 ; 5 B is (C(R 2 )2)n; n is 0 or 1; and RI, R 2 , R 4 , W, R 3 , G-J, Q, T, U, V and m are as defined in Formula I; and pharmaceutically acceptable salts and individual stereoisomers thereof. 10 Additional embodiments of the invention are CGRP antagonists of Formula I which include compounds of the Formula Ic: 1 Q U R2R (R3

R

2 N G NH

R

2 2R4 R O O 0 0 Ic wherein: 15 R1, R 2 , R 4 , W, R 3 , G-J, Q, T, U, V and m are as defined in Formula I; and pharmaceutically acceptable salts and individual stereoisomers thereof. Additional embodiments of the invention are CGRP antagonists of Formula I which also include compounds of the Formula Id: R1Q U 2 R O 3) 1

_

9 R2 W N G NH R2A R 4 20 0 0 Id wherein: A is C(R 2 )2, 0, S(O)m or NR 2 ; RI, R 2 , R 4 , W, R 3 ,G-J, Q, T, U, V and m are as defined in Formula I; 25 and pharmaceutically acceptable salts and individual stereoisomers thereof. - 11 - WO 2004/092166 PCT/US2004/010851 Additional embodiments of the invention are CGRP antagonists of Formula I which include compounds of the Formula le: R1 Q)-T U N

(R

3

)

1

_

9 R2N -Y R4 N G NH R 0 O Ie 5 wherein: A is C(R 2 )2, 0, S(O)m or NR 2 ; RI, R 2 , R 4 , W, R 3 , G-J, Q, T, U, V and m are defined in Formula I; and pharmaceutically acceptable salts and individual stereoisomers thereof. 10 Further embodiments of the invention are CGRP antagonists of Formulae Ia -Ie, wherein: RI is selected from: 15 1) H, CI-C 6 alkyl, C3-6 cycloalkyl and heterocycle, unsubstituted or substituted with one or more substituents independently selected from: a) Cl-6 alkyl, b) C3-6 cycloalkyl, 20 c) aryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , d) heteroaryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , e) heterocycle, unsubstituted or substituted with 1-5 substituents 25 where the substituents are independently selected from R 4 , f) (F)pCl.3 alkyl, g) halogen, h) OR 4 . i) O(CH2)sOR 4 30 j) C0 2

R

4 - 12 - WO 2004/092166 PCT/US2004/010851 k) CN, 1) NR 1 0

R

1 1 , and m) O(CO)R 4 ; and 5 2) aryl or heteroaryl, unsubstituted or substituted with one or more substituents independently selected from: a) C1-6 alkyl, b) C3-6 cycloalkyl, c) (F)pC1-3 alkyl, 10 d) halogen, e) OR 4 , f) C0 2

R

4 . g) (CO)NR 1 ORil, h) SO2NR1 0 RIl, 15 i) N(R10) SO2Ril, j) S(O)mR 4 , k) CN, 1) NR 10

RI

1 , and, m) O(CO)R 4 ; 20

R

2 is selected from: 1) H, CO-C6 alkyl, C2-C 6 alkynyl, C3-6 cycloalkyl and heterocycle, unsubstituted or substituted with one or more substituents independently selected from: 25 a) C1-6 alkyl, b) C3-6 cycloalkyl, c) aryl, unsubstituted or substituted with 1-5 sustituents where the substituents are independently selected from R 4 , d) heteroaryl, unsubstituted or substituted with 1-5 substituents 30 where the substituents are independently selected from R 4 , e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , f) (F)pC1-3 alkyl, g) halogen, - 13 - WO 2004/092166 PCT/US2004/010851 h) OR 4 , i) O(CH 2 )sOR 4 , j) C0 2

R

4 , k) S(O)mR 4 , 5 1) CN, m) NR 10

R

1 1 , and n) O(CO)R 4 ; and 2) aryl or heteroaryl, unsubstituted or substituted with one more substituents 10 independently selected from: a) C1-6 alkyl, b) C3-6 cycloalkyl, c) (F)pC1-3 alkyl, d) halogen, 15 e) OR 4 , f) CO 2

R

4 , g) (CO)NR 10

R

1 1 , h) SO2NR1 0

R

1 , i) N(R10) SO2R il, 20 j) S(O)mR 4 , k) CN, 1) NRIOR 1, and m) O(CO)R 4 , 25 or, any two independent R2 on the same or adjacent atoms may be joined together to form a ring selected from cyclobutyl, cyclopentenyl, cyclopentyl, cyclohexenyl, cyclohexyl, phenyl, naphthyl, thienyl, thiazolyl, thiazolinyl, oxazolyl, oxazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrimidyl, pyrazinyl, pyrrolyl, pyrrolinyl, morpholinyl, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S-dioxide, 30 azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridyl, furanyl, dihydrofuranyl, dihydropyranyl and piperazinyl; R1 0 and R 1 I are independently selected from: H, C1-6 alkyl, (F)pC1-6 alkyl, C3-6 cycloalkyl, aryl, heteroaryl and benzyl, unsubstituted or substituted with halogen, hydroxy or C1-C6 alkoxy, - 14- WO 2004/092166 PCT/US2004/010851 where RIO and R 1 1 may be joined together to form a ring selected from: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 5 R 4 is independently selected from: H, C1-6 alkyl, (F)pC1-6 alkyl, C3-6 cycloalkyl, aryl, heteroaryl and benzyl, unsubstituted or substituted with halogen, hydroxy or C1-C6 alkoxy; W is 0, NR 4 or C(R 4 )2; 10 G-J is selected from: N, such that when G-J is so defined the following structure forms: ,T- U Q// \ -~N NH o 15

N-C(R

5 )2, such that when G-J is so defined the following structure forms: RQ'-TN1 QU

R

5 -N y NH 0 20

C=C(R

5 ), such that when G-J is so defined the following structure forms: - 15 - WO 2004/092166 PCT/US2004/010851 Q U

R

5 V NH 0 C=N, such that when G-J is so defined the following structure forms: Q U N - NH 5 0 C=C(R5)-C(R 5 )2, such that when G-J is so defined the following structure forms: R5U

R

5 NH 0 10

C(R

5

)-C(R

5

)=C(R

5 ), such that when G-J is so defined the following structure forms: Q U

R

5 R5 NH

'R

5 0 15 - 16 - WO 2004/092166 PCT/US2004/010851 N-C(R5)2-C(R5)2 , such that when G-J is so defined the following structure forms: 50 U R5 R

R

5 NH Rs N 0 ,and 5 N-C(R 5

)=C(R

5 ), such that when G-J is so defined the following structure forms: / U R 5 NH N 10 Q, T, U and V are each independently a carbon atom or a nitrogen atom wherein at least one but no more than three of Q, T, U and V are nitrogen atoms, of which one may be optionally an N oxide, and wherein when any of Q, T, U, or V is a carbon atom it is unsubstituted or substituted where the substituents are independently selected from R 6 ; 15 R 6 is independently selected from H and: a) C1-6 alkyl, b) C3-6 cycloalkyl, c) (F)pC1-3 alkyl, d) halogen, 20 e) OR 4 , 0 C0 2

R

4 , g) (CO)NR 10

R

11 , h) SO 2

NR

10 RII, i) N(R 1 0)SO 2 RI1, 25 j) S(O)mR 4 , - 17- WO 2004/092166 PCT/US2004/010851 k) CN, 1) NRIOR 1 1 and m) O(CO)R 4 ; and 5 R 5 is independently selected from H, substituted or unsubstituted CI-C3 alkyl, CN, OR 4 ,

N(R

4 )2 and C0 2

R

4 ;

R

3 is independently selected from H, substituted or unsubstituted CI-C3 alkyl, F, CN and C0 2

R

4 ; 10 p is 0 to 2q+1, for a substituent with q carbons mis 0 to 2; s is 1 to 3; and pharmaceutically acceptable salts and individual stereoisomers thereof. 15 Still further embodiments of the invention are CGRP antagonists of Formulae la Ie, wherein: R is selected from: 20 1) H, CI-C 6 alkyl, C 3 -6 cycloalkyl and heterocycle, unsubstituted or substituted with one or more substituents independently selected from: a) C1-6 alkyl, b) C3-6 cycloalkyl, c) phenyl, unsubstituted or substituted with 1-5 substituents 25 where the substituents are independently selected from R4, d) heteroaryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R4, 30 and where heteroaryl is selected from: imidazole, isoxazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, and thiazole; - 18- WO 2004/092166 PCT/US2004/010851 e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from

R

4 , and where heterocycle is selected from: azetidine, dioxane, dioxolane, morpholine, oxetane, piperazine, piperidine, 5 pyrrolidine, tetrahydrofuran, and tetrahydropyran; f) (F)pCl-3 alkyl, g) halogen, h) OR 4 , i) O(CH)OR 4 , 10 j) C0 2

R

4 k) CN, 1) m) O(CO)R 4 ; 15 2) aryl or hetewoaryl, selected from: phenyl, imidazole, isoxazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, and thiazole, unsubstituted or substituted with one or more substituents independently selected from: 20 a) C 1 6 alkyl, b) C 3

-

6 cycloalkyl, c) (F)pC1-3 alkyl, d) halogen, e) OR 4 , 25 f) C0 2

R

4 , g) (CO)NR IOR 1 1 , h) S0 2

NRIOR

1 1 , j) S(O)mR 4 , 30 k) CN, 1) NRIORI 1 , and m) O(CO)R 4 ;

R

2 is selected from: - 19 - WO 2004/092166 PCT/US2004/010851 1) H, CO-C 6 alkyl, C3-6 cycloalkyl and heterocycle, unsubstituted or substituted with one or more substituents independently selected from: a) C1-6 alkyl, 5 b) C3-6 cycloalkyl, c) phenyl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from d) heteroaryl, unsubstituted or substituted with 1-5 substituents 10 where the substituents are independently selected from and where heteroaryl is selected from: benzimidazole, benzothiophene, furan, imidazole, indole, isoxazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, and triazole; 15 e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , and where heterocycle is selected from: azetidine, imidazolidine, imidazoline, isoxazoline, isoxazolidine, morpholine, oxazoline, oxazolidine, oxetane, pyrazolidine, pyrazoline, pyrroline, tetrahydrofuran, tetrahydropyran, thiazoline, and 20 thiazolidine; f) (F)pCl-3 alkyl, g) halogen, h) OR 4 . i) O(CHD)OR 4 , 25 j) C0 2

R

4 , k) CN, 1) NR 10

R

1 1 , and m) O(CO)R 4 ; and 30 2) aryl or heteroaryl, selected from: phenyl, benzimidazole, benzothiophene, furan, imidazole, indole, isoxazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, and triazole; - 20 - WO 2004/092166 PCT/US2004/010851 unsubstituted or substituted with one or more substituents independently selected from: a) Cl-6 alkyl, b) C3-6 cycloalkyl, 5 c) (F)pCl-3 alkyl, d) halogen, e) OR 4 , f) C0 2

R

4 , g) (CO)NR1 0 RII, 10 h) SO2NR 1 0 Ri", i) N(R1 0 ) SO2R I1, j) S(O)mR 4 , k) CN, 1) NR10RIl, and 15 m) O(CO)R 4 , or, any two independent R 2 on the same or adjacent atoms may be joined together to form a ring selected from cyclobutyl, cyclopentenyl, cyclopentyl, cyclohexenyl, cyclohexyl, phenyl, naphthyl, thienyl, thiazolyl, thiazolinyl, oxazolyl, oxazolinyl, imidazolyl, 20 imidazolinyl, imidazolidinyl, pyridyl, pyrimidyl, pyrazinyl, pyrrolyl, pyrrolinyl, morpholinyl, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S-dioxide, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridyl, furanyl, dihydrofuranyl, dihydropyranyl and piperazinyl, 25 RIO and RI I are independently selected from: H, C1-6 alkyl, (F)pCl-6 alkyl, C3-6 cycloalkyl, aryl, heteroaryl and benzyl, unsubstituted or substituted with halogen, hydroxy or Cl-C6 alkoxy, where RIO and R1 I may be joined together to form a ring selected from: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 ; 30

R

4 is independently selected from: H, Ci-6 alkyl, (F)pC1-6 alkyl, C3-6 cycloalkyl, aryl, heteroaryl and phenyl, unsubstituted or substituted with hydroxy or CI-C6 alkoxy; W is NR 4 or C(R 4 )2; - 21 - WO 2004/092166 PCT/US2004/010851 5 G-J and Q-T-U-V are as follows: G-J is N and Q-T-U-V is N=C(R 6

)-C(R

6

)=C(R

6 ), such that when G-J and Q-T-U-V are so defined the following structure forms: R 6

R

6 RN R6 N H 0 10 G-J is N and Q-T-U-V is C(R 6

)=N-C(R

6

)=C(R

6 ), such that when G-J and Q-T-U-V are so defined the following structure forms:

R

6 R6 N R S N NH 15 G-J is N and Q-T-U-V is C(R 6

)=C(R

6

)-N=C(R

R

6

R

6 N R6 -N NH 0 - 22 - WO 2004/092166 PCT/US2004/010851 G-J is N and Q-T-U-V is C(R6)=C(R 6

)-C(R

6 )=N, such that when G-J and Q-T-U-V are so defined the following structure forms:

R

6 R R 6 -/ \ N N NH 5 0 G-J is N and Q-T-U-V is C(R 6

)=C(R

6 )-N=N, such that when G-J and Q-T-U-V are so defined the following structure forms: 10 R6 R6 N N .N YN H 0 G-J is N and Q-T-U-V is C(R 6

)=N-C(R

6 )=N, such that when G-J and Q-T-U-V are so defined the following structure forms: 15

R

6 RSN

R

6 / \ N N yNH G-J is N and Q-T-U-V is N=C(R6)-C(R 6 )=N, such that when G-J and Q-T-U-V are so defined the following structure forms: - 23 - WO 2004/092166 PCT/US2004/010851 R6 N~ R N -N NH 0 , 5 G-J is N-C(R 5 )2 and Q-T-U-V is C(R 6

)=C(R

6

)-C(R

R

6 R6 R6

R

5 I-~ R5 t N - -N yNH 0 10 G-J is N-C(R 5 )2 and Q-T-U-V is C(R 6 )= N-C(R 6

)=C(R

R

6 N R 6 R R6 -- N NH 0 15 G-J is C=C(R 5 ) and Q-T-U-V is C(R 6

)=C(R

6

)-C(R

6 )=N, such that when G-J and Q-T-U-V are so defined the following structure forms: - 24- WO 2004/092166 PCT/US2004/010851 R6 R6 R6

R

5 I N NH 0 G-J is C=C(R 5 ) and Q-T-U-V is C(R 6

)=N-C(R

6

)=C(R

6 ), such that when G-J and Q-T-U-V are so defined the following structure forms: 5

R

6 N R 6 R5 R NH o G-J is C=N and Q-T-U-V is C(R 6

)=C(R

6

)-C(R

6 )=N, such that when G-J and Q-T-U-V are so defined the following structure forms: 10 R6 RE3 R6 N N NH O , 0 G-J is C=N and Q-T-U-V is C(R 6

)=N-C(R

6

)=C(R

6 ), such that when G-J and Q-T-U-V are so defined the following structure forms: 15 - 25 - WO 2004/092166 PCT/US2004/010851

R

6 N R 6 N R6 + NH 0 G-J is N-C(R 5 )2-C(R 5 )2 and Q-T-U-V is C(R 6

)=C(R

6

)-C(R

6 )=N, such that when G-J and Q-T U-V are so defined the following structure forms: 5 R6 R5 I N R5 NH R5N 0 , and G-J is N-C(R 5 )2-C(R 5 )2 and Q-T-U-V is C(R 6

)=N-C(R

6

)=C(R

6 ), such that when G-J and Q-T U-V are so defined the following structure forms: 10

R

6 N R 6 R5R5 R 5 NH

R

5 O0;

R

6 is independently selected from H and: 15 a) Cl-6 alkyl, b) C3-6 cycloalkyl, c) (F)pCl-3 alkyl, d) halogen, e) OR 4 , 20 f) C0 2

R

4 , -26- WO 2004/092166 PCT/US2004/010851 g) (CO)NR 10 R 11, h) SO 2

NR

10

R

1 1 , i) N(R 10 ) SO 2 RI I j) S(O)mR 4 , 5 k) CN, I) NR1 0 R 1 1 , and m) O(CO)R 4 ;

R

5 is independently selected from H, substituted or unsubstituted C1-C3 alkyl, CN, OR 4 , 10 N(R 4 )2 and C0 2

R

4 ;

R

4 ; p is 0 to 2q+1, for a substituent with q carbons 15 m is 0 to 2; s is 1 to 3; and pharmaceutically acceptable salts and individual stereoisomers thereof. 20 Another embodiment of the invention includes CGRP antagonists which include compounds of Formula II: R1 QU B N R2 25 wherein: B, G, J, Q, T, U, V, W, X, Y, RI, R 2 , R 3 and R 4 are as defined in Formula I, and pharmaceutically acceptable salts and individual diastereomers thereof. - 27 - WO 2004/092166 PCT/US2004/010851 It is to be understood that where one or more of the above recited structures or substructures recite multiple substituents having the same designation each such variable may be the same or different from each similarly designated variable. For example, R 2 is recited four times in Formula I, and each R 2 in Formula I may independently be any of the substructures 5 defined under R 2 . The invention is not limited to structures and substructures wherein each R 2 must be the same for a given structure. The same is true with respect to any variable appearing multiple time in a structure or substructure. The compounds of the present invention may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, 10 diastereomeric mixtures and individual diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the ambit of this invention. The present invention is meant to 15 comprehend all such isomeric forms of these compounds. Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers. The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology 20 disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in 25 the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the 30 added chiral residue. The racemic mixture of the compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art. - 28 - WO 2004/092166 PCT/US2004/010851 Alternatively, any enantiomer of a compound may be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art. As will be appreciated by those of skill in the art, not all of the R1O and RI 1 5 substituents are capable of forming a ring structure. Moreover, even those substituents capable of ring formation may or may not form a ring structure. Also as appreciated by those of skill in the art, halo or halogen as used herein are intended to include chloro, fluoro, bromo and iodo. As used herein, "alkyl" is intended to mean linear, branched and cyclic structures 10 having no double or triple bonds. Thus C1-6alkyl is defined to identify the group as having 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement, such that C1-6alkyl specifically includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl and hexyl. "Cycloalkyl" is an alkyl, part or all of which which forms a ring of three or more atoms. CO or Coalkyl is defined to identify the presence of a direct covalent bond. 15 The term "alkenyl" means linear or branched structures and combinations thereof, of the indicated number of carbon atoms, having at least one carbon-to-carbon double bond, wherein hydrogen may be replaced by an additional carbon-to-carbon double bond. C2-6alkenyl, for example, includes ethenyl, propenyl, 1-methylethenyl, butenyl and the like. The term "alkynyl" means linear or branched structures and combinations thereof, 20 of the indicated number of carbon atoms, having at least one carbon-to-carbon triple bond. Thus C2-6alkynyl is defined to identify the group as having 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement, such that C2-6alkynyl specifically includes 2-hexynyl and 2-pentynyl. As used herein, "aryl" is intended to mean any stable monocyclic or bicyclic carbon ring of up to 7 members in each ring, wherein at least one ring is aromatic. Examples of 25 such aryl elements include phenyl, napthyl, tetrahydronapthyl, indanyl, or biphenyl. The term "heterocycle" or "heterocyclic", as used herein except where noted, represents a stable 5- to 7-membered monocyclic- or stable 8- to 1-membered bicyclic heterocyclic ring system which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, 0 and S, and 30 wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heterocyclic groups include, but are not limited to, azetidine, chroman, - 29 - WO 2004/092166 PCT/US2004/010851 dihydrofuran, dihydropyran, dioxane, dioxolane, hexahydroazepine, imidazolidine, imidazolidinone, imidazoline, imidazolinone, indoline, isochroman, isoindoline, isothiazoline, isothiazolidine, isoxazoline, isoxazolidine, morpholine, morpholinone, oxazoline, oxazolidine, oxazolidinone, oxetane, 2-oxohexahydroazepin, 2-oxopiperazine, 2-oxopiperidine, 2 5 oxopyrrolidine, piperazine, piperidine, pyran, pyrazolidine, pyrazoline, pyrrolidine, pyrroline, quinuclidine, tetrahydrofuran, tetrahydropyran, thiamorpholine, thiazoline, thiazolidine, thiomorpholine and N-oxides thereof. The term "heteroaryl", as used herein except where noted, represents a stable 5- to 7-membered monocyclic- or stable 9- to 10-membered fused bicyclic heterocyclic ring system 10 which contains an aromatic ring, any ring of which may be saturated, such as piperidinyl, partially saturated, or unsaturated, such as pyridinyl, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, 0 and S, and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined 15 heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure. Examples of such heteroaryl groups include, but are not limited to, benzimidazole, benzisothiazole, benzisoxazole, benzofuran, benzothiazole, benzothiophene, benzotriazole, benzoxazole, carboline, cinnoline, furan, furazan, imidazole, indazole, indole, indolizine, isoquinoline, isothiazole, isoxazole, 20 naphthyridine, oxadiazole, oxazole, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazine, triazole, and N-oxides thereof. The term "alkoxy," as in CI-C6 alkoxy, is intended to refer to include alkoxy groups of from I to 6 carbon atoms of a straight, branched and cyclic configuration. Examples 25 include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like. The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, 30 commensurate with a reasonable benefit/risk ratio. As used herein, "pharmaceutically acceptable salts" refer to derivatives wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; -30- WO 2004/092166 PCT/US2004/010851 and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric 5 and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like. The number of certain variables present in certain instances is defined in terms of 10 the number of carbons present. For example, variable "p" is occasionally defined as follows: "p is 0 to 2q+1, for a substituent with q carbons". Where the substituent is "(F)pC1-3 alkyl" this means that when there is one carbon, there are 2(1) + 1 = 3 fluorines. When there are two carbons, there are 2(2) + 1 = 5 fluorines, and when thre are three carbons there are 2(3) = 1 = 7 fluorines. 15 When variables G and J are presented or depicted as "G-J" this indicates that G and J together represent a particular moiety. G-J may represent a single ring atom or various arrangements of multiple ring atoms. For instance, G-J is at times herein defined as the single ring atom N, and is at other times defined as multiple ring atoms C=C(R5), C=N, and so forth. Similarly, when variables Q, T, U and V are presented or depicted as "Q-T-U-V" 20 this indicates that these variables together represent a particular moiety. Here, Q-T-U-V may represent various arrangements of multiple ring atoms, for instance N=C(R 6

)-C(R

6

)=C(R

6 ),

C(R

6

)=N-C(R

6

)=C(R

6 ) and C(R 6

)=C(R

6

)-N=C(R

6 ), among others. When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids 25 include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p toluenesulfonic acid, and the like. In one aspect of the invention the salts are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids. It will be understood that, 30 as used herein, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts. Exemplifying the invention is the use of the compounds disclosed in the Examples and herein. Specific compounds within the present invention include a compound - 31 - WO 2004/092166 PCT/US2004/010851 which selected from the group consisting of the compounds disclosed in the following Examples and pharmaceutically acceptable salts thereof and individual diastereomers thereof. The subject compounds are useful in a method of antagonism of CGRP receptors in a patient such as a mammal in need of such antagonism comprising the administration of an 5 effective amount of the compound. The present invention is directed to the use of the compounds disclosed herein as antagonists of CGRP receptors. In addition to primates, especially humans, a variety of other mammals can be treated according to the method of the present invention. Another embodiment of the present invention is directed to a method for the 10 treatment, control, amelioration, or reduction of risk of a disease or disorder in which the CGRP receptor is involved in a patient that comprises administering to the patient a therapeutically effective amount of a compound that is an antagonist of CGRP receptors. The present invention is further directed to a method for the manufacture of a medicament for antagonism of CGRP receptors activity in humans and animals comprising 15 combining a compound of the present invention with a pharmaceutical carrier or diluent. The subject treated in the present methods is generally a mammal, for example a human being, male or female, in whom antagonism of CGRP receptor activity is desired. The term "therapeutically effective amount" means the amount of the subject compound that will elicit the biological or medical response of a tissue, system, animal or human that is being sought 20 by the researcher, veterinarian, medical doctor or other clinician. As used herein, the term "treatment" refers both to the treatment and to the prevention or prophylactic therapy of the mentioned conditions, particularly in a patient who is predisposed to such disease or disorder. The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which 25 results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Such term in relation to pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the 30 ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient - 32 - WO 2004/092166 PCT/US2004/010851 must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The terms "administration of" and or "administering a" compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the 5 invention to the individual in need of treatment. The utility of the compounds in accordance with the present invention as antagonists of CGRP receptor activity may be demonstrated by methodology known in the art. Inhibition of the binding of 1 25 I-CGRP to receptors and functional antagonism of CGRP receptors were determined as follows: 10 NATIVE RECEPTOR BINDING ASSAY: The binding of 1 25 I-CGRP to receptors in SK-N-MC cell membranes was carried out essentially as described (Edvinsson et al. (2001) Eur. J. Pharmacol. 415, 39-44). Briefly, membranes (25 tg) were incubated in 1 mL of binding buffer [10 mM HEPES, pH 7.4, 5 mM MgCl 2 and 0.2% bovine serum albumin (BSA)] containing 10 pM 1 2 5 I-CGRP andantagonist. After incubation at room temperature for 3 h, the 15 assay was terminated by filtration through GFB glass fibre filter plates (Millipore) that had been blocked with 0.5% polyethyleneimine for 3 h. The filters were washed three times with ice-cold assay buffer, then the plates were air dried. Scintillation fluid (50 pL) was added and the radioactivity was counted on a Topcount (Packard Instrument). Data analysis was carried out by using Prism and the Ki was determined by using the Cheng-Prusoff equation (Cheng & Prusoff 20 (1973) Biochem. Pharmacol. 22, 3099-3108). NATIVE RECEPTOR FUNCTIONAL ASSAY: SK-N-MC cells were grown in minimal essential medium (MEM) supplemented with 10% fetal bovine serum, 2 mM L glutamine, 0.1 mM non-essential amino acids, 1 mM sodium pyruvate, 100 units/mL penicillin and 100 [g/ml streptomycin at 37 'C, 95% humidity, and 5% CO 2 . For cAMP assays, cells were 25 plated at 5 x 10 5 cells/well in 96-well poly-D-lysine-coated plates (Becton-Dickinson) and cultured for - 18 h before assay. Cells were washed with phosphate-buffered saline (PBS, Sigma) then pre-incubated with 300 piM isobutylmethylxanthine in serum-free MEM for 30 min at 37 'C. Antagonist was added and the cells were incubated for 10 min before the addition of CGRP. The incubation was continued for another 4 min, then the cells were washed with PBS 30 and processed for cAMP determination according to the manufacturer's recommended protocol. Maximal stimulation over basal was defined by using 100 nM CGRP. Dose-response curves were generated by using Prism. Dose-ratios (DR) were calculated and used to construct full Schild plots (Arunlakshana & Schild (1959) Br. J. Pharmacol. 14, 48-58). - 33 - WO 2004/092166 PCT/US2004/010851 RECOMBINANT RECEPTOR: Human CRLR (Genbank accession number L76380) was subcloned into the expression vector pIREShyg2 (BD Biosciences Clontech) as a 5'NheI and 3' PmeI fragment. Human RAMPI (Genbank accession number AJ001014) was subcloned into the expression vector plRESpuro2 (BD Biosciences Clontech) as a 5'NheI and 5 3'NotI fragment. 293 cells (human embryonic kidney cells; ATCC #CRL-1573) were cultured in DMEM with 4.5 g/L glucose, 1 mM sodium pyruvate and 2 mM glutamine supplemented with 10% fetal bovine serum (FBS), 100 units/mL penicillin and 100 ug/ml streptomycin, and maintained at 37 *C and 95% humidity. Cells were subcultured by treatment with 0.25% trypsin with 0.1% EDTA in HBSS. Stable cell line generation was accomplished by co-transfecting 10 10 ug of DNA with 30 ug Lipofectamine 2000 (Invitrogen) in 75 cm 2 flasks. CRLR and RAMPI expression constructs were co-transfected in equal amounts. Twenty-four hours after transfection the cells were split 1:5 and selective medium (growth medium + 300 ug/mL hygromycin and 1 ug/mL puromycin) was added the following day. A clonal cell line was generated by single cell deposition utilizing a FACS Vantage SE (Becton Dickinson). Growth 15 medium was adjusted to 150 ug/ml hygromycin and 0.5 ug/mL puromycin for cell propagation. RECOMBINANT RECEPTOR BINDING ASSAY: Cells expressing recombinant human CRLR/RAMP1 were washed with PBS and harvested in harvest buffer containing 50 mM HEPES, 1 mM EDTA and Complete protease inhibitors (Roche). The cell suspension was disrupted with a laboratory homogenizer and centrifuged at 48,000 g to isolate 20 membranes. The pellets were resuspended in harvest buffer plus 250 mM sucrose and stored at 70 "C. For binding assays, 10 ug of membranes were incubated in 1 mL binding buffer (10 mM HEPES, pH 7.4, 5 mM MgC 2 , and 0.2% BSA) for 3 hours at room temperature containing 10 pM 1 2 5 -hCGRP (Amersham Biosciences) and inhibitor. The assay was terminated by filtration through 96-well GFB glass fiber filter plates (Millipore) that had been blocked with 0.05% 25 polyethyleneimine. The filters were washed 3 times with ice-cold assay buffer (10 mM HEPES, pH 7.4). Scintillation fluid was added and the plates were counted on a Topcount (Packard). Non-specific binding was determined and the data analysis was carried out with the apparent dissociation constant (Ki) determined by using a non-linear least squares fitting the bound CPM data to the equation below: 30 Y~otb = (Xma_--_Ymi)(%lm, % / 100) + Yn + (Yma - Ymir)(100-%Ima/100) I + ([Drug] / Ki (1 + [Radiolabel) / Kd) " Where Y is observed CPM bound, Ymax is total bound counts, Y min is non specific bound counts, (Y max - Y min) is specific bound counts, % I max is the maximum percent inhibition, % I min is the minimum percent inhibition, radiolabel is the probe, and the Kd is the apparent - 34 - WO 2004/092166 PCT/US2004/010851 dissociation constant for the radioligand for the receptor as determined by Hot saturation experiments. RECOMBINANT RECEPTOR FUNCTIONAL ASSAY: Cells were plated in complete growth medium at 85,000 cells/well in 96-well poly-D-lysine coated plates 5 (Corning) and cultured for - 19 h before assay. Cells were washed with PBS and then incubated with inhibitor for 30 min at 37 'C and 95% humidity in Cellgro Complete Serum-Free/Low Protein medium (Mediatech, Inc.) with L-glutamine and 1 g/L BSA. Isobutyl-methylxanthine was added to the cells at a concentration of 300 uM and incubated for 30 min at 37 'C. Human ca-CGRP was added to the cells at a concentration of 0.3 nM and allowed to incubate at 37 'C for 10 5 min. After ax-CGRP stimulation the cells were washed with PBS and processed for cAMP determination utilizing the two-stage assay procedure according to the manufacturer's recommended protocol (cAMP SPA direct screening assay system; RPA 559; Amersham Biosciences). Dose response curves were plotted and IC 50 values determined from a 4-parameter logistic fit as defined by the equation y = ((a-d)/(1+(x/c)b) + d, where y = response, x = dose, a 15 max response, d = min response, c = inflection point and b = slope. In particular, the compounds of the following examples had activity as antagonists of the CGRP receptor in the aforementioned assays, generally with a Ki or IC 50 value of less than about 50 [tM. Such a result is indicative of the intrinsic activity of the compounds in use as antagonists of CGRP receptors. 20 The ability of the compounds of the present invention to act as CGRP antagonists makes them useful pharmacological agents for disorders that involve CGRP in humans and animals, but particularly in humans. The compounds of the present invention have utility in treating, preventing, ameliorating, controlling or reducing the risk of one or more of the following conditions or 25 diseases: headache; migraine; cluster headache; chronic tension type headache; pain; chronic pain; neurogenic inflammation and inflammatory pain; neuropathic pain; eye pain; tooth pain; diabetes; non-insulin dependent diabetes mellitus; vascular disorders; inflammation; arthritis; bronchial hyperreactivity, asthma; shock; sepsis; opiate withdrawal syndrome; morphine tolerance; hot flashes in men and women; allergic dermatitis; encephalitis; brain trauma; 30 epilepsy; neurodegenerative diseases; skin diseases; neurogenic cutaneous redness, skin rosaceousness and erythema; tinnitus; inflammatory bowel disease, irritable bowel syndrome, cystitis; and other conditions that may be treated or prevented by antagonism of CGRP receptors. Of particular importance is the acute or prophylactic treatment of headache, including migraine and cluster headache. - 35 - WO 2004/092166 PCT/US2004/010851 The subject compounds are further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions noted herein. The subject compounds are further useful in a method for the prevention, 5 treatment, control, amelioration, or reduction of risk of the aforementioned diseases, disorders and conditions in combination with other agents. The compounds of the present invention may be used in combination with one or more other drugs in the treatment, prevention, control, amelioration, or reduction of risk of diseases or conditions for which compounds of Formula I or the other drugs may have utility, 10 where the combination of the drugs together are safer or more effective than either drug alone. Such other drug(s) may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of Formula I. When a compound of Formula I is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such other drugs and the compound of Formula I is 15 preferred. However, the combination therapy may also include therapies in which the compound of Formula I and one or more other drugs are administered on different overlapping schedules. It is also contemplated that when used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the 20 present invention include those that contain one or more other active ingredients, in addition to a compound of Formula I. For example, the present compounds may be used in conjunction with an anti inflammatory or analgesic agent or an anti-migraine agent, such as an ergotamine or 5-HT 1 agonists, especially a 5-HTIB/D agonist, for example sumatriptan, naratriptan, zolmitriptan, 25 eletriptan, almotriptan, frovatriptan, donitriptan, and rizatriptan; a cyclooxygenase inhibitor, such as a selective cyclooxygenase-2 inhibitor, for example rofecoxib, etoricoxib, celecoxib, valdecoxib or paracoxib; a non-steroidal anti-inflammatory agent or a cytokine-suppressing anti inflammatory agent, for example with a compound such as aspirin, ibuprofen, ketoprofen, fenoprofen, naproxen, indomethacin, sulindac, meloxicam, piroxicam, tenoxicam, lornoxicam, 30 ketorolac, etodolac, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, diclofenac, oxaprozin, apazone, nimesulide, nabumetone, tenidap, etanercept, tolmetin, phenylbutazone, oxyphenbutazone, diflunisal, salsalate, olsalazine or sulfasalazine and the like; or a steroidal analgesic. Similarly, the instant compounds may be administered with a pain - 36 - WO 2004/092166 PCT/US2004/010851 reliever such as acetaminophen, phenacetin, codeine, fentanyl, sufentanil, methadone, acetyl methadol, buprenorphine or morphine. Additionally, the present compounds may be used in conjunction with an interleukin inhibitor, such as an interleukin-1 inhibitor; an NK-1 receptor antagonist, for example 5 aprepitant; an NMDA antagonist; an NR2B antagonist; a bradykinin- I receptor antagonist; an adenosine Al receptor agonist; a sodium channel blocker, for example lamotrigine; an opiate agonist such as levomethadyl acetate or methadyl acetate; a lipoxygenase inhibitor, such as an inhibitor of 5-lipoxygenase; an alpha receptor antagonist, for example indoramin; an alpha receptor agonist; a vanilloid receptor antagonist; an mGluR5 agonist, antagonist or potentiator; a 10 GABA A receptor modulator, for example acamprosate calcium; nicotinic antagonists or agonists including nicotine; muscarinic agonists or antagonists; a selective serotonin reuptake inhibitor, for example fluoxetine, paroxetine, sertraline, duloxetine, escitalopram, or citalopram; a tricyclic antidepressant, for example amitriptyline, doxepin, protriptyline, desipramine, trimipramine, or imipramine; a leukotriene antagonist, for example montelukast or zafirlukast; an 15 inhibitor of nitric oxide or an inhibitor of the synthesis of nitric oxide. Also, the present compounds may be used in conjunction with ergot alkaloids, for example ergotamine, ergonovine, ergonovine, methylergonovine, metergoline, ergoloid mesylates, dihydroergotamine, dihydroergocornine, dihydroergocristine, dihydroergocryptine, dihydro-I-ergocryptine, dihydro-a-ergocryptine, ergotoxine, ergocomine, ergocristine, 20 ergocryptine, I-ergocryptine, O-ergocryptine, ergosine, ergostane, bromocriptine, or methysergide. Additionally, the present compounds may be used in conjunction with a beta adrenergic antagonist such as timolol, propanolol, atenolol, or nadolol, and the like; a MAO inhibitor, for example phenelzine; a calcium channel blocker, for example flunarizine, 25 nimodipine, lomerizine, verapamil, nifedipine, prochlorperazine or gabapentin; neuroleptics such as olanzapine and quetiapine; an anticonvulsant such as topiramate, zonisamide, tonabersat, carabersat or divalproex sodium; an angiotensin 11 antagonist, for example losartan and candesartan cilexetil; an angiotensin converting enzyme inhibitor such as lisinopril; or botulinum toxin type A. 30 The present compounds may be used in conjunction with a potentiator such as caffeine, an H2-antagonist, simethicone, aluminum or magnesium hydroxide; a decongestant such as phenylephrine, phenylpropanolamine, pseudoephedrine, oxymetazoline, epinephrine, naphazoline, xylometazoline, propylhexedrine, or levo-desoxy-ephedrine; an antitussive such as - 37 - WO 2004/092166 PCT/US2004/010851 codeine, hydrocodone, caramiphen, carbetapentane, or dextromethorphan; a diuretic; a prokinetic agent such as metoclopramide or domperidone, and a sedating or non-sedating antihistamine. In a particularly preferred embodiment the present compounds are used in conjunction with an anti-migraine agent, such as: an ergotamine; a 5-HT 1 agonist, especially a 5 5 HTIB/D agonist, in particular, sumatriptan, naratriptan, zolmitriptan, eletriptan, almotriptan, frovatriptan, donitriptan and rizatriptan; and a cyclooxygenase inhibitor, such as a selective cyclooxygenase-2 inhibitor, in particular, rofecoxib, etoricoxib, celecoxib, meloxicam, valdecoxib or paracoxib. The above combinations include combinations of a compound of the present 10 invention not only with one other active compound, but also with two or more other active compounds. Likewise, compounds of the present invention may be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which compounds of the present invention are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, 15 contemporaneously or sequentially with a compound of the present invention. When a compound of the present invention is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of the present invention is preferred. Accordingly, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a 20 compound of the present invention. The weight ratio of the compound of the compound of the present invention to the other active ingredient(s) may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present invention is combined with another agent, the weight ratio of the 25 compound of the present invention to the other agent will generally range from about 1000:1 to about 1:1000, or from about 200:1 to about 1:200. Combinations of a compound of the present invention and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used. In such combinations the compound of the present invention and other active 30 agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s), and via the same or different routes of administration. The compounds of the present invention may be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, -38- WO 2004/092166 PCT/US2004/010851 subcutaneous injection, or implant), by inhalation spray, nasal, vaginal, rectal, sublingual, or topical routes of administration and may be formulated, alone or together, in suitable dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles appropriate for each route of administration. In addition to the treatment of warm 5 blooded animals the compounds of the invention are effective for use in humans. The pharmaceutical compositions for the administration of the compounds of this invention may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. 10 In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. As used herein, the term "composition" is 15 intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, 20 dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable 25 preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia; and lubricating agents, for 30 example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Patents 4,256,108; 4,166,452; and 4,265,874 to form - 39 - WO 2004/092166 PCT/US2004/010851 osmotic therapeutic tablets for control release. Oral tablets may also be formulated for immediate release, such as fast melt tablets or wafers, rapid dissolve tablets or fast dissolve films. Formulations for oral use may also be presented as hard gelatin capsules wherein 5 the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for 10 example sodium carboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example 15 heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or 20 more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, 25 hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing 30 or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. The pharmaceutical compositions of the invention may also be in the form of oil in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, - 40 - WO 2004/092166 PCT/US2004/010851 or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally- occurring gums, for example gum acacia or gum tragacanth, naturally occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products 5 of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. 10 The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 15 1,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. 20 The compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. 25 For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are employed. Similarly, transdermal patches may also be used for topical administration. The pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in the 30 treatment of the above mentioned pathological conditions. In the treatment, prevention, control, amelioration, or reduction of risk of conditions which require antagonism of CGRP receptor activity an appropriate dosage level will generally be about 0.01 to 500 mg per kg patient body weight per day which can be administered in single or multiple doses. A suitable dosage level may be about 0.01 to 250 mg/kg per day, - 41 - WO 2004/092166 PCT/US2004/010851 about 0.05 to 100 mg/kg per day, or about 0.1 to 50 mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5 or 5 to 50 mg/kg per day. For oral administration, the compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0. 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 5 500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds may be administered on a regimen of 1 to 4 times per day, or may be administered once or twice per day. When treating, preventing, controlling, ameliorating, or reducing the risk of headache, migraine, cluster headache, or other diseases for which compounds of the present 10 invention are indicated, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight, given as a single daily dose or in divided doses two to six times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 1.0 milligrams to about 1000 milligrams, or from about 1 milligrams to 15 about 50 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors 20 including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy. Several methods for preparing the compounds of this invention are illustrated in 25 the following Schemes and Examples. Starting materials are made according to procedures known in the art or as illustrated herein. The compounds of the present invention can be prepared readily according to the following Schemes and specific examples, or modifications thereof, using readily available starting materials, reagents and conventional synthesis procedures. In these reactions, it is also 30 possible to make use of variants which are themselves known to those of ordinary skill in this art but are not mentioned in greater detail. The general procedures for making the compounds claimed in this invention can be readily understood and appreciated by one skilled in the art from viewing the following Schemes. - 42 - WO 2004/092166 PCT/US2004/010851 The synthesis of intermediates and final compounds may be conducted as described in Schemes 1-16. REACTION SCHEMES 5 The preparation of final compounds proceeds through intermediates such as those of Formula III and Formula IV, and representative syntheses are described herein. \ Q U

R

2 N- (R), 9 N> NH 2 R A-B R4 HN G NH III IV 10 In general, intermediates of the Formulae III and IV can be coupled through a urea linkage as shown in Scheme 1. Amine intermediate 1 can be converted to a reactive carbamate, for example p-nitrophenylcarbamate 2, which is subsequently reacted with an amine like that of intermediate 3 to produce urea 4. Other activated intermediates known to those 15 skilled in the art can be used to prepare compounds like 4. For example, amine I can be directly acylated with the appropriate carbamoyl chloride. 20 25 - 43 - WO 2004/092166 PCT/US2004/010851 SCHEME i R, CI O 0 ii 0 N ON/ N

NH

2 2NH R2 THF, Et 3 N, 0 -C R 2 O 12 2 0 R3 O \ NH NO 2 HN NNH N R1 3 R6N R 3 0 Et 3 N, O C - +r R 2 N N N 0 - N 4 5 The synthesis of compounds represented by Intermediate IV can be accomplished by procedures similar to those described in Henning et al., J. Med. Chem., 1987, 30, 814-819; Carpino et al., WO 96/35713; Brown et al., J. Chem. Soc. 1957, 682-686; Barlin et al., Aust. J. Chem. 1982, 35 (11), 2299-2306; and references cited therein. Additionally, the synthesis of compounds represented by Intermediate IV can be 10 accomplished according to Schemes 2-6. For example, a diamino heterocycle, such as 2,3 diaminopyridine 5, can be reductively alkylated with ketones such as 6 to give the monalkylated product 2 (Scheme 2). Ring closure with carbonyldiimidazole furnishes imidazolone 8. Final deprotection under standard conditions gives the intermediate 9. 15 20 - 44 - WO 2004/092166 PCT/US2004/010851 SCHEME 2 R6

R

6 NaBH(OAc) 3 , DCE N

H

2 N N - BocN N H2 N BocN H NH 2

H

2

N

5 6 7 R3 -R6 R3 CDI /I N HCI

CH

3 CN * BocN N NH CH 3 0H

R

6 8 0 N 2 HCI HN N H 9 0 5 Alternatively, as described in Scheme 3, a suitably protected 4-ketopiperidine like 10 can be reductively alkylated with the appropriate a-amino ester, for example by allylglycine methyl ester (11, R 6 =H), which then would furnish 12. Treatment with trimethylsilyl isocyanate yields hydantoin 13. Oxidative cleavage of the terminal double bond can be accomplished under standard conditions to afford aldehyde 14, which can be cyclized in the presence of hydrazine in 10 warm acetic acid to deliver 15. Removal of the protecting group gives compounds like 16. - 45 - WO 2004/092166 PCT/US2004/010851 SCHEME 3 R H 2 N CO 2 Me

R

3 Cbz-I 11 1 CbzN 0 RN CbzN NH 10 NaHB(OAc) 3 , DCE O2 R6 __ 6 O"

R

3 0 TMS-NCO, DMAP TiH Os0 4 , NalO 4 CbzN N THF THF / H 2 0 R6 CbzN N H

NH

2

NH

2 N 14 R 6 AcOH CbzN N NH 15 0 3 R

H

2 , Pd/C /~ S HN N

C

2

H

5 OH Y(NH 16 0 5 In Scheme 4, a suitably protected 4-aminopiperidine 17 can be arylated by a SNAr reaction, for example using methyl 2-bromopyrazine-3-carboxylate. The resulting product 18 can be converted to an acyl azide via acyl hydrazide 19. Thermal rearrangement of the acyl azide (Curtius rearrangement) can occur with concomitant ring closure to produce 20. Final deprotection under standard conditions gives the desired heterocycles 21. 10 - 46 - WO 2004/092166 PCT/US2004/010851 SCHEME 4 Br R R3 Br N/ RR 3 N/

CH

3 0 2 C F BnN NH 2 - BnN N 2-propanol, reflux H CO 2

CH

3 17 18

R

6 R3 N// NH2NH2 N 1) HCI/NaNO 2 , OOC, H 2 0 HN BnN N

H

2

C

2

H

5 0H H CONHNH 2 2) 2-methoxyethanol 19 1800C R6 R6 3 N 3 N R R N BnN N 20% Pd/C, H 2 , HN N N

CH

3 0H 20 0 21 0 5 Additional heterocycles can be synthesized in a similar manner. For example, a heterocycle carboxaldehyde, such as 22 (J. Med. Chem. 1998, 31, 2136-45) in Scheme 5, can be reductively aminated with amines such as 23 to give the monoalkylated product 24. 10 Deprotection with acid and ring closure with carbonyldiimidazole furnishes pyridodihydropyrimidinone 26. Final deprotection under standard basic conditions gives the product 27. -47 - WO 2004/092166 PCT/US2004/010851 SCHEME 5

-

DCE, AcOH -NR O NaHB(OAc) 3 - EtO 2 C-N NH OHC\/02CID N / EtO 2 C-N

NH

2 BocHN BocHN 22 23 24 N R 6 TFA NH CDI, (C 2

H

5

)

3 N DCM EtO2C-NDH 2 N CH 3 CN 25 /-N R 6 - R 6 EtO 2 C-N D N( R N NaOH N H rel HN N N( / 26 0 reflux 27 0 5 A similar synthetic strategy can be used to construct the related pyridodihydropyrimidinone of formula 29 starting from the commercially available aldehyde 28. R R 6 -R 6 OHC NR\ O HN N N BocHN 28 />-NH 29 0 10 Alternatively, addition of a suitably protected amine, such as 31, to the commercially available chloropyridine 30, followed by nitrile reduction affords the diamine 33 (Scheme 6). This diamino heterocycle can be reductively alkylated with ketones such as 6 to give the monoalkylated product 34. Ring closure with carbonyldiimidazole furnishes pyridodihydropyrimidinone 35. Final deprotection with trifluoroacetic acid gives the product 36. 15 -48- WO 2004/092166 PCT/US2004/010851 SCHEME 6

-R

6

R

6 NC (C 2

H

5

)

3 N, DMA NC R LAH, THF N C0 NH 2 NH __ - 32 MeO OMe OMe 31 MeO -IR DOE, AcGH R

H

2 N NaHB(OAc) 3 BocN NH RN NH BocN 0 OMe 6 34 OMe R3 MeO MeO CDI, (C 2

H

5

)

3 N BocNa N R/TEA

CH

3 CN 0 N OMe MeO R R A HN N N 36 O A similar synthetic strategy can be used to construct the related pyridodihydropyrimidinone of 5 formula 38 starting from the known nitrile 37. N R 6 N N- R 6 NC 30 HJ N NlQ F 37 /-NH 38 0 -49- WO 2004/092166 PCT/US2004/010851 Caprolactams can be assembled following an olefin metathesis strategy as outlined in Scheme 7. 2,4-Dimethoxybenzylamine hydrochloride is alkylated with 2,3 dibromopropene under mild basic conditions to give amine 39. (2R)-2 {[(benzyloxy)carbonyl]amino}pent-4-enoic acid 4Q, prepared in one step from commercially 5 available D-allyl glycine according to known procedures (J. Chem. Soc., 1962, 3963-3968), can be coupled to amine 30 under a variety of conditions to give amide 41. A variety of transition metal catalyzed cross couplings can be performed on the vinyl bromide, for example palladium mediated arylations with phenylboronic acid and sodium carbonate, yielding styrene derivative 42. Ring-closing metathesis occurs in the presence of the Grubbs second generation ruthenium 10 catalyst in dichloromethane with mild heating to afford lactam 43. Removal of the dimethoxybenzyl group and hydrogenation with in situ protection of the primary amine gives the corresponding saturated lactam 45. After selective alkylation of the amide nitrogen with various electrophiles such as alkyl bromides, deprotection under acidic conditions yields compounds of the general formula 47. 15 - 50 - WO 2004/092166 PCT/US2004/010851 SCHEME 7 Br MeO OMe Br MeO OMe Et 3 N, CH 2

CI

2

NH

2 -HCI Br NH 31 39 HO 0 MeO OMe NHCbz '7 40 Br N O ArB(OH) 2 , Na 2 CO3 EDC, CH 2 Cl 2 Pd(Ph 3

P)

4 , THF/H 2 0, 60 0C NHCbz OMe MeO OMe MeO O N Grubbs i Ru cat. N NH 0H 4.00NHCbz CH2Cl2, 40 -C R 'NHCbz 42 R H HO TFA N H 2 , Pd/C N CH2Cl2 "NHCbz Boc20, EtOAc .""NHBoc R 44R 4 R%0 ' 0 R'Br N TFA N NaH, DMF -"NHBoc H2C ""NH 2 46 47 Mes-N N-Mes Grubbs 11 = Ru PCy 3 -51 - WO 2004/092166 PCT/US2004/010851 Alternatively, a C6-aryl group can be introduced as outlined in Scheme 8. Addition of nitromethane to the known glutamic acid derived aldehyde 48 (Tetrahedron Asymmetry, 1998, 3381-94), followed by in situ elimination affords nitro olefin 49. Addition of the aryl group via a boronic acid derivative, or similar equivalent, can be accomplished in a stereoselective manner 5 through chiral ligand-Rh catalysis. Concomitant nitro reduction and benzyl ester hydrogenolysis affords the amino acid 51. Ring closure under standard conditions, followed by removal of a single tert-butoxycarbonyl group furnishes the lactam 45. Intermediates such as 51 can be further processed as in Scheme 9. - 52 - WO 2004/092166 PCT/US2004/010851 SCHEMEE 8

NO

2

CH

3 , PhCH 3 Ph CO2Bn tetramethyl- 0

CO

2 Bn guanidine; 0 2 N O OHC "N(Boc) 2 then "'N(Boc) 2 48 MsCI, Et 3 N, 0OC 49 Ph Rh(acac)(C 2

H

4

)

2 Oh 0 (S)-BINAP 0 2 N 0 O N(Boc)2 55psi

H

2 dioxane, H 2 0, Pd/C, EtOH NaHCO 3

B(OH)

2 X R 50 R 0

H

2 N HO EDC, DCM H -""N(Boc) 2 HOAT, Et 3 N N .Il[N BOC)2-.N(Boc)2 R1 52 R H O 1) NaH, DMF R 0 TFA, DCM N

R

1 X N -"'NHBoc 2) TFA, DCM

""'NH

2 45 47 R R 5 Alternatively, amino acid 51 can be alkylated, either reductively or via an SN2 displacement, to afford intermediates such as 53 (Scheme 9). Ring closure under standard conditions, followed by protecting group removal furnishes the lactam 55. - 53 - WO 2004/092166 PCT/US2004/010851 SCHEME 9

H

2 N HO O NaB(OAc) 3 H RiN HO EDC, DCM "'N(Boc) 2 DCE, RiaCHO ""N(Boc) 2 HOAT, Et 3 N OR R 51 EtOH, (iPr) 2 NEt R 53 RlaCH 2 X R O N N N(Boc)2 TFA, DCM

'NH

2 R 4 R 55 5 Variation at the 6-position of the caprolactams can be introduced by employing a similar strategy (Scheme 10). Ring-closing metathesis can be performed directly on vinyl bromide 41 using the Grubbs second generation ruthenium catalyst to give cyclic vinyl bromide 56. Removal of the dimethoxybenzyl group and palladium-mediated cross coupling, in this case with a boronic acid, furnishes compounds of the general formula 58. The transformation of 57 to 58 is not limited to 10 boronic acid derivatives. After standard hydrogenation, the amide nitrogen can be selectively alkylated with various electrophiles, for example alkyl bromides, using sodium hydride as base. Deprotection yields lactams of the general formula 61. - 54 - WO 2004/092166 PCT/US2004/010851 SCHEME 10 OMe MeO OMe MeO

N

0 N O Grubbs 11 Ru cat. N Br 'NHCbz

CH

2

CI

2 , 40 0C Br "NHCbz 41 H O TFA N R 2

B(OH)

2 , Na 2

CO

3 , Pd(OAc) 2 CH2C2 Br"NHCbz (m-NaSO 3 Ph) 3 P, DMF/H 2 0, 80 0C 57 H H O N H 2 , Pd/C N -"'NHCbz -"'NHBoc

R

2 K Boc 2 0, PhMe/MeOH R2 58 59 R %1 0R 0 R'Br N TFA N '-""NHBoc - ' "'"NH 2 NaH, DMF R2

CH

2 CI2 R2 60 61 MesNyMes Mes-N N'Me Grubbs 11 = CRu 5 Alternatively, addition of a Grignard or similar reagent, to the nitro olefin 49, followed by nitro reduction and benzyl ester hydrogenolysis affords various amino acids such as 63 (Scheme 11). Ring closure with EDC furnishes caprolactam 64. Final deprotection with trifluoroacetic acid gives the product 65. 10 - 55 - WO 2004/092166 PCT/US2004/010851 SCHEME 11 Ph (Ph

O

2 N 0 NR 2 -MgCI 0 2 N 0 R 2 49 62 55psi H 2 0 Pd/C, EtOH H 2 N HO EDC, DCM -2;N(Boc) 2 HOAT, Et 3 N R R2 63 64 TFA, DCM HN

-'IIINH

2 65 5 The C7-position of the caprolactam can be varied as outlined in Scheme 12. Addition of the nitroalkane to an aldehyde R 2 CHO, affords an alcohol such as 66. Concomitant nitro reduction and benzyl ester hydrogenolysis affords the amino acid 67. Ring closure under standard conditions, followed by removal of the tert-butoxycarbonyl groups furnishes the lactam 69. - 56 - WO 2004/092166 PCT/US2004/010851 SCHEME 12 Ph P (Po R 2 CHO HO R2 Ph 0 2 N 0 tetramethyl- 0 2 N O 'N(Boc) 2 guanidine ,""(c R 50 \ 66 R R2 HO H HO EDC, DCM Pd/C, 55 psi H 2

H

2 Ns 0HOA t3N "'jjN(BOC) 2

HAE

3 R 67 R2H 0 2 N HO HO TFA, DCM HO 0''.1N(Boc)2 HO 0 'N H2 R 68 ' R6 5 The oxazepanones can be prepared according to Scheme 13. (S)-(-)-Styrene oxide (or substituted derivatives) 70 can be opened by reaction with various primary amines in isopropanol solvent to afford the corresponding amino alcohols 71. Selective N-protection followed by boron trifluoride etherate catalized aziridine opening of 23 (prepared according to known procedures: J. 10 Chem. Soc., Perkins Trans. 1, 1994, 7, 807-816) provides ether 74. Hydrolysis of the methyl ester, selective amine deprotection, and amide bond formation with diphenylphosphoryl azide gives 26, which after standard hydrogenation conditions yields amine 77. 15 - 57 - WO 2004/092166 PCT/US2004/010851 SCHEME 13 R1 O NH

R

1

NH

2 Boc 2 O i-PrOH, reflux OH Et 3 N, CH 2

CI

2 R 70 R 71 0 1 MeO 1 NBoc 7 "NCbz NBoc ___________OMe OH BF 3 -OEt 2 , CHC1 3 O NHCbz R 72 R Ri NaOH NBoc OH a) TFA, CH 2

CI

2

THF/H

2 0 O b) DPPA, DMF NHCbz R 75 R1 R1 N

H

2 , Pd/C N EtOH R 76 77 5 The 3-acetyl caprolactam derivatives can be prepared as outlined in Scheme 14. Lactam 78 (prepared according to known procedures: J. Med. Chem., 1988, 31, 422-428) can be alkylated selectively at the amide nitrogen with a variety of electrophiles, such as alkyl bromides, using sodium hydride as base. C-alkylation is achieved by generation of the enolate-with lithium diisopropylamide followed by quenching with tert-butyl bromoacetate, giving ester 79. 10 Deprotection of the carboxyl group is accomplished with trifluoroacetic acid. Coupling of the - 58 - WO 2004/092166 PCT/US2004/010851 resultant carboxylic acid with amine 9 under standard conditions affords 3-acetyl lactams of the general formula 82 SCHEME 14 5 HO R Br O

R

1 Br O NaH, DMF LDA, THF, -78 0 C R 78 R 79 R11 0 R 0 N TFA N O .CH 2 Cl 2 OH R 80 R 81 Ri1 N R 3 0 EDC, HOBT i-Pr 2 NEt, DMF N H R8O N

R

7 8 Piperidinones are prepared as outlined in Scheme 15. Commercially available 10 hydroxypyridine 89 can be selectively N-alkylated using various electrophiles with cesium carbonate. Palladium-mediated cross coupling with different aryl, heteroaryl, and alkyl groups affords the substituted pyridinones. Platinum catalyzed hydrogenation at 56 psi results in both reduction of the olefins and the nitro group, giving diastereomeric mixtures of the primary amine 92. Urea formation under standard conditions with the appropriate amine (eg, 9) yields the final 15 targets 93. - 59 - WO 2004/092166 PCT/US2004/010851 SCHEME 15

R

1 OH R 1 Br, Cs 2

CO

3 N O Br NO 2 DMF Br NO 2 89 90

R

2

B(OH)

2 , i-Pr 2 NH, Pd(OAc) 2 N 0 H 2 , Pt/C (m-NaSO 3 Ph) 3 P, DMF/H 2 0, 80 C R2 NO2 HOAc 91 Y1 C0 O

CK-ONO

2 N 0 a) THF, Et 3 N,0 O"C N 0 R2 NH 2 b) R 3 0 R 2 NH R 3 0 92HN' NN N~ NN Rt,/ 93 R61 Et 3 N, 0 C -+ rt 5 Diazepinone derivatives can be prepared as shown in Scheme 16. Following amine protection of the commercially available diazepinone 94, alkylation of various electrophiles with sodium hydride gives substituted amides 96. Removal of the Cbz group and reductive amination of various aldehydes or alkylation of different halides affords the disubstituted diazepinones, such as 98, and final deprotection of the primary amine with 10 trifluoroacetic acid yields the urea coupling precursor 99. 15 - 60- WO 2004/092166 PCT/US2004/010851 SCHEME 16 H H O N Boc 2 O, Et 3 N (N R'Br

NH

2

CHC

2 KNHBoc N CH2C2 N NaH, DMF Cbz 0 C - rt Cbz 94 95 R R' 1 0 % 0 N H 2 , Pd/C (N NaCNBH 3 NHBoc NHBoc N MeOH N

R

2 CHO, MeOH Cbz H 96 97 R1 R1 A 0 % 0 N ~ TFAN NHBoc 2

NH

2 R2 Rk2 98 99 5 In some cases the final product may be further modified, for example, by manipulation of substituents. These manipulations may include, but are not limited to, reduction, 10 oxidation, alkylation, acylation, and hydrolysis reactions which are commonly known to those skilled in the art. Moreover, in some cases the order of carrying out the foregoing reaction schemes may be varied to facilitate the reaction or to avoid unwanted reaction products. INTERMEDIATES AND EXAMPLES 15 The following examples are provided so that the invention might be more fully understood. These examples are illustrative only and should not be construed as limiting the invention in any way. -61- WO 2004/092166 PCT/US2004/010851 INTERMEDIATE I N 2 HCI -HN N NH 0 2-Oxo- 1 -(4-piperidinyl)-2,3-dihydro- I H-imidazo[4,5-blpyridine dihydrochloride 5 Step A. 2-Amino-3-[(1-t-butoxycarbonylpiperidin-4-yl)amino)pyridine Sodium triacetoxyborohydride (14.5 g, 68.7 mmol) was added to a solution of 2,3-diaminopyridine (5.00 g, 45.8 mmol) and N-(t-butoxycarbonyl)-4-piperidone (9.58 g, 48.1 mmol) in dichloroethane (75 mL) at room temperature. After 5 h, additional sodium triacetoxyborohydride was added (1.8 g) and again after another 2.5 h. The reaction was stirred 10 overnight, and quenched with 5% aqueous sodium hydroxide. This was extracted with methylene chloride, and washed with 5% aqueous sodium hydroxide, water and saturated sodium chloride solution. After drying over sodium sulfate, the solution was filtered and evaporated to give the crude product. This was purified by chromatorgraphy (silica gel, 3 to 5% methanol in methylene chloride gradient elution), which gave the title compound (4.44 g). MS 293 (M+1) 15 1H NMR (500 MHz, CD30D) 6 7.32 (dd, J=1, 5 Hz, IH), 6.85 (dd, J=1, 8 Hz, IH), 6.59 (dd, J=5, 8 Hz, IH), 4.04 (d, J=13 Hz, 2H), 3.46 (m, 1H), 2.98 (br s, 2H), 2.01 (dd, J=2, 12 Hz, 2H), 1.46 (s, 9H), 1.37 (qd, J=4, 12 Hz, 2H). Step B. 2-Oxo-1-(1-t-butoxycarbonylpiperidin-4-yl)-2,3-dihydro- 1H-imidazo[4,5-blpyridine 20 Carbonyldiimidazole (0.70 g, 4.33 mmol) was added to a solution of 2-amino-3 [(1-t-butoxycarbonylpiperidin-4-yl)amino]pyridine (1.15 g, 3.93 mmol) in acetonitrile (150 mL) at room temperature. After several hours, an additional amount of carbonyldiimidazole was added (0.81 g), and the reaction stirred overnight. The acetonitrile was evaporated in vacuo, the residue partitioned between water and chloroform, and the organic phase washed with saturated 25 brine and dried over magnesium sulfate. The crude product was purified by chromatography (silica gel, 1.2 to 2.5% methanol in methylene chloride gradient elution), which gave the title compound (1.09 g). 1H NMR (500 MHz, CDCl3) 8 9.39 (br s, 1H), 8.04 (dd, J=1, 5 Hz, 1H), 7.33 (dd, J=1, 8 Hz, 1H), 6.99 (dd, J=5, 8 Hz, 1H), 4.50 (m, IH), 4.32 (br s, 2H), 2.86 (br s, 2H), 2.20 (m, 2H), 1.86 (d, J=12 Hz, 2H), 1.50 (s, 9H). - 62 - WO 2004/092166 PCT/US2004/010851 Step C. 2-Oxo- 1-(4-piperidinyl)-2,3-dihydro- 1H-imidazo[4,5-blpyridine dihydrochloride 2-Oxo- 1-(1 -t-butoxycarbonylpiperidin-4-y)-2,3-di hydro-1H-imidazo[4,5 b]pyridine (1.03 g, 3.23 mmol) was dissolved in methanol (25 mL) and a solution of 2N 5 hydrochloric acid in ether (8 mL) was added at room temperature. After 2 h, the volatiles were removed in vacuo, to give the title compound (0.92 g). MS 219 (M + 1). 1H NMR (500 MHz, CD30D) 8 8.01 (dd, J=1, 6 Hz, 1H), 7.83 (d, J=8 Hz, 1H), 7.28 (dd, J=6, 8 Hz, 1H), 4.60 (m, IH), 3.59 (d, J=12 Hz, 2H), 3.21 (t, J=12 Hz, 2H), 2.70 (dq, J=4, 13 Hz, 2H), 2.12 (d, J=13 Hz, 2H). 10 INTERMEDIATE 1A 0 Cl N N NH o N 15 4-(2-Oxo-2,3-dihydro- 1H-imidazor4,5-blpvyridin- 1 -yl)piperidine- 1 -carbonyl chloride Phosgene (20% wt. in toluene; 1.8 mL, 3.43 mmol) was added to a suspension of 2-oxo-1-piperidinium-4-yl-2,3-dihydro-1H-imidazo[4,5-b]pyridin-4-ium dichloride (100 mg, 0.343 mmol) and 2,6-lutidine (0.50 mL, 4.293 mmol) in dichloromethane (5 mL) at 0 'C. After 2 h, the solution was added to saturated aqueous sodium bicarbonate and extracted with ethyl 20 acetate. The organic layer was washed with water (2x), saturated brine, dried over magnesium sulfate, filtered and concentrated. Dichloromethane (10 mL) was added, and the mixture was filtered to give the title compound as a solid (48 mg). MS 281 (M+1). 'H NMR (500 MHz,

(CD

3

)

2 SO) 8 11.58 (s, 1H), 7.90 (d, J= 5.1 Hz, 1H), 7.67 (d, J= 7.6 Hz, 1H), 7.01-6.99 (m, 1H), 4.52-4.46 (m, 1H), 4.31-4.23 (m, 2H), 3.38-3.33 (m, IH), 3.19-3.14 (m, 1H), 2.32-2.24 (m, 2H), 25 1.84-1.81 (m, 2H). - 63 - WO 2004/092166 PCT/US2004/010851 INTERMEDIATE 2 00 HN N >NH 1 -Piperidin-4-yl- 1,3-dihydro-2H-imidazo [4,5-b]pyridin-2-one 4-oxide Step A. tert-Butvl 4-(4-oxido-2-oxo-2,3-dihydro-IH-imidazo[4,5-blpyridin-1-yl)piperidine-1 5 carboxylate 2-Oxo-1-(1-t-butoxycarbonylpiperidin-4-yl)-2,3-dihydro-IH-imidazo[4,5 b]pyridine (63 mg, 0.198 mmol) was dissolved in 1,2-dichloroethane (10 mL) and 3 chloroperoxybenzoic acid (137 mg, 0.792 mmol) was added at 0 oC. The reaction was warmed to room temperature and stirred for 4 h. The reaction was quenched with saturated aqueous 10 sodium bicarbonate and sodium thiosulfate, extracted with methylene chloride (3x), dried over sodium sulfate, filtered and evaporated to give the title compound (45 mg). MS 335.1 (M + 1). Step B. I -Piperidin-4-yl- 1, 3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 4-oxide tert-Butyl 4-(4-oxido-2-oxo-2,3-dihydro- IH-imidazo[4,5-b]pyridin- 1 15 yl)piperidine-1-carboxylate (45 mg, 0.135 mmol) was dissolved in dichloromethane (10 mL) and trifluoroacetic acid (5 mL) was added at room temperature. After 3 h, the volatiles were removed in vacuo to give the title compound as its TFA salt. MS 235.2 (M + 1). INTERMEDIATE 3 N 2 HBr - HN N NH 20 0 2-Oxo-3-(4-piperidinyl)-2,3-dihydro- 1H-imidazo[4,5-clpyridine dihydrobromide Step A. Ethyl 4-(pyridin-4-ylami no)piperidine- 1 -carboxylate A solution of ethyl 4-aminopiperidine-1-carboxylate (2.20 g, 12.7 mmol), 4 bromopyridine (3.47 g, 17.8 mmol), sodium t-butoxide (4.54 g, 47.2 mmol), 2,2' - 64 - WO 2004/092166 PCT/US2004/010851 bis(diphenylphosphino)-1,1'-binaphthyl (0.398 g, 0.639 mmol) and palladium acetate (0.143 g, 0.639 mmol) in toluene (40 mL) was heated at 60 OC overnight. The reaction was cooled and partitioned between ethyl acetate and water. The aqueous layer was washed 3 times with methylene chloride, and the combined organic layers dried over sodium sulfate. The crude 5 product was purified by chromatography (silica gel, 0 to 10% {5% ammonium hydroxide in methanol} in methylene chloride gradient elution), which gave the title compound (1.3 g, 41% yield). Step B. Ethyl 4-[(3-nitropyrin-4-yl)aminolpiperidine- 1 -carboxylate 10 A solution of ethyl 4-(pyridin-4-ylamino)piperidine-1-carboxylate (1.30 g, 5.21 mmol) in 90% sulfuric acid (17 mL) was cooled to 0 OC. To this was added 70% nitric acid (1.2 mL) in 90% sulfuric acid (8 mL). The reaction was stirred at 0 OC for 1.5 h, then poured into ice water (150 mL). Solid sodium carbonate was added to render the solution basic. This mixture was extracted four times with methylene chloride, dried, filtered and concentrated. The crude 15 product was purified by chromatography (silica gel, 0 to 10% {5% ammonium hydroxide in methanol} in methylene chloride gradient elution), which gave the title compound (1.09 g, 71% yield). Step C. Ethyl 4-[(3-aminopyrin-4-yl)aminolpiperidine- 1 -carboxylate 20 Ethyl 4-[(3-nitropyrin-4-yl)aminolpiperidine-1-carboxylate (1.09 g, 3.70 mmol) in ethanol was hydrogenated (1 atm hydrogen) over 30% palladium on carbon (300 mg) for 4 h. The reaction was filtered through celite and concentrated in vacuo, to give the title compound (0.98 g, 100%). 25 Step D. Ethyl 4-[(2-oxo-2,3-dihydro- 1H-imidazol[4,5-clpyridin-1-yl)piperidine-1-carboxylate A solution of ethyl 4-[(3-aminopyrin-4-yl)amino]piperidine- 1 -carboxylate (0.98 g, 3.70 mmol) and carbonyldiimidazole (1.80 g, 11.1 mmol) in tetrahydrofuran (40 mL) was refluxed until starting material was consumed. The solvent was removed in vacuo and the crude product purified by chromatography (silica gel, 0 to 10% {5% ammonium hydroxide in 30 methanol} in methylene chloride gradient elution). Fractions containing product were dissolved in methylene chloride and washed with saturated sodium carbonate to remove co-eluting imidazole. The organic phase was dried over sodium sulfate, filtered and concentrated to give the title compound (0.360 g, 33% yield). - 65 - WO 2004/092166 PCT/US2004/010851 Step E. 2-Oxo- 1-(4-piperidinyl)-2,3-dihydro- 1IH-imidazol [4,5-clpyridine dihydrobromide A solution of ethyl 4-[(2-oxo-2,3-dihydro-IH-imidazol[4,5-c]pyridin-1 yl)piperidine-1-carboxylate (0.120 g, 0.413 mmol) in 30% hydrogen bromide/acetic acid (1 mL) was heated at 70 OC overnight. The reaction was cooled and concentrated in vacuo. The 5 resulting solid was triturated with methylene chloride and dried, giving the title compound (0.123 g, 78% yield). 1H NMR (500 MHz, CD30D) 8 8.48 (d, J=6 Hz, 1H), 8.46 (s,IH), 7.94 (d, J=6 Hz, IH), 4.80 (m, IH), 3.60 (d, J=10 Hz, 2H), 3.30 (m, partially obscured by solvent peak), 2.81 (dq, J=4,12 Hz, 2H), 2.16 (d, J=12 Hz, 2H). 10 INTERMEDIATE 4 N H N N N H 0 2-Oxo-3-(4-piperidinyl)-2,3-dihydro-IH-imidazo[4,5-clpyridine Step A. 4-Amino-3-[(I -benzylpiperidin-4-yl)amino)pyridine A mixture of 3,4-diaminopyridine (1.1 g, 10.1 mmol), 1-benzyl-4-piperidone (3.2 15 g, 16.9 mmol) sodium triacetoxyborohydride (4.0 g, 18.9 mmol), and acetic acid (10.7 mL) in dichloroethane (10 mL) was stirred for about 6 days at room temperature. The reaction was concentrated to near dryness, and partitioned between chloroform (5 x 50 mL) and IN sodium hydroxide (50 mL). The organic phase was dried over magnesium sulfate and concentrated to give the title compound (2.8 g). MS 283 (M+1). 20 Step B. 2-Oxo-3-( -benzylpiperidin-4-yl)-2,3-dihydro- IH-imidazo[4,5-clpyridine A solution of 4-amino-3- [(1-benzylpiperidin-4-yl)amino)pyridine (2.8 g, 9.9 mmol) and carbonyldiimidazole (3.0 g, 18.5 mmol) in tetrahydrofuran (100 mL) was refluxed overnight. The reaction was cooled, concentrated and partitioned between chloroform (500 mL) 25 and saturated sodium carbonate (100 mL). The organic phase was dried over magnesium sulfate and concentrated to give the title compound (2.8 g). MS 209 (M+1). - 66 - WO 2004/092166 PCT/US2004/010851 Step C. 2-Oxo-3-(4-piperidinyl)-2,3-dihydro- IH-imidazo[4,5-clpyridine A solution of 2-oxo-3-(I -benzylpiperidin-4-yl)-2,3-dih ydro- l-1-imidazo[4,5 c]pyridine (0.5 g, 1.6 mmol) in methanol (250 mL) was shaken with 20% Pd(OH)2 under a hydrogen atmosphere for 48 h at room temperature. The reaction was filtered and concentrated 5 to give the title compound as a white solid (0.3 g). MS 219 (M+1). INTERMEDIATE 5 N HN N >NH 0 2-Oxo-1-(4-piperidinyl)-2,3-dihydro-IH-imidazo[4,5-blpyrazine 10 Step A. Methyl 3- [(1 -benzylpiperidin-4-yl)aminolpyrazine-2-carboxylate A mixture of methyl 2-bromopyrazine-3-carboxylate (J. Med. Chem., 1969, 12, 285) (2.2 g, 10.1 mmol) and 4-amino-1-benzylpiperidine (2.0 g, 10.5 mmol) was refluxed in 2 propanol overnight. Thin layer chromatography (10% methanol in ethyl acetate) showed the reaction was complete. The solvent was evaporated, and the crude product dissolved in 15 chloroform (100 mL), which was washed with saturated sodium carbonate solution (20 mL), and dried over magnesium sulfate. The title compound was obtained as a gum (3.8 g). MS 327 (M+1). Step B. 3-[(1-Benzylpiperidin-4-yl)aminolpyrazine-2-carbohydrazide 20 A mixture of methyl 3- [(1 -benzylpiperidin-4-yl)amino]pyrazine-2-carboxylate (3.0 g, 9.2 mmol) and hydrazine hydrate (6 mL) in ethanol (100 mL) was refluxed with stirring for 2 h. The reaction was cooled and concentrated to give the title compound (3.0 g). MS 327 (M+1). 25 Step C. 2-Oxo-1 -(1 -benzylpiperidin-4-yl)-2,3-dihydro-IH-imidazofr4,5-blpyrazine 3-[(I-Benzylpiperidin-4-yl)amino]pyrazine-2-carbohydrazide (3.0 g, 9.2 mmol) was dissolved in 1N HCI (20 mL) and water (40 mL), and cooled to 0 0 C. To this was added aqueous sodium nitrite (0.8 g, 11.6 mmol) in water (5 mL). After 0.5 h sodium bicarbonate was added and the basic solution extracted with chloroform (5 x 50 mL), which was dried over - 67 - WO 2004/092166 PCT/US2004/010851 magnesium sulfate. The crude acyl azide was dissolved in methoxyethanol (20 mL) and heated at 180 0 C for 3 h. The progress of the reaction was monitored by thin layer chromatography (10% methanol in chloroform). The reaction was cooled and concentrated, and the crude product purified by preparative thin layer chromatography (silica gel, 75:25 tetrahydrofuran:hexane) to 5 give the title compound (1.7 g). MS 310 (M+1). Step D. 2-Oxo-1-(4-piperidinyl)-2,3-dihydro-IH-imidazo[4,5-blpyrazine 2-Oxo-1-(1-benzylpiperidin-4-yl)-2,3-dihydro-IH-imidazo[4,5-b]pyrazine (1.7 g, 5.5 mmol) was dissolved in methanol (100 mL) and hydrogenated over 20% palladium on carbon 10 (0.5 g) at 55 psi hydrogen overnight. The catalyst was filtered and solvent evaporated to give the title compound (1.5 g). INTERMEDIATE 6 N HCI - HN N e NH 15 0 7-Piperidin-4-yl-7,9-dihydro-8H-purin-8-one hydrochloride Step A. 4-Amino-5-[(1-t-butoxycarbonylpiperidin-4-yl)amino)pyrimidine A mixture of 4,5-diaminopyrimidine (1.0 g, 9.1 mmol), N-(t-butoxycarbonyl)-4 piperidone (3.0 g, 15 mmol) and sodium triacetoxyborohydride (1.2 g, 5.6 mmol) in 20 dichloroethane (60 mL) was stirred at room temperature for 3 d. The reaction was partitioned between chloroform (200 mL) and 3N sodium hydroxide (30 mL). After drying over magnesium sulfate, the organic phase was concentrated to give the title compound as a tan gum. MS 294 (M+1) 25 Step B. 7-(I-Benzylpiperidin-4-yl)-7,9-dihydro-8H-purin-8-one The crude product from Step A, 4-amino-5-[(I-t-butoxycarbonylpiperidin-4 yl)amino)pyrimidine, was refluxed with carbonyldiimidazole (3.0 g, 18 mmol) in tetrahydrofuran (250 mL) for 2 d, cooled and concentrated. The crude product was dissolved in ethyl acetate (25 - 68 - WO 2004/092166 PCT/US2004/010851 50 mL), which in four crops gave the title compound as a white crystalline solid (1.3 g). MS 320 (M+1) Step C. 7-Piperidin-4-yl-7,9-dihydro-8H-purin-8-one hydrochloride 5 A mixture of 7-(1-benzylpiperidin-4-yl)-7,9-dihydro-8H-purin-8-one (1.2 g, 3.7 mmol) in 4N hydrogen chloride in dioxane (50 mL), was stirred vigorously at room temperature for 3 h. The reaction was concentrated in vacuo to give the title compound as a white solid. MS 220 (M+1) 10 INTERMEDIATE 7 N H N N NNH 0 5-Piperidin-4-yl-5,7-dihydro-6H-imidazo[4,5-clpyridazin-6-one Step A. Benzyl 4-1 [1 -(methoxycarbonyl)but-3-en-1 -yllamino I piperidine- I -carboxylate Sodium triacetoxyborohydride (11.2 g, 52.6 mmol) was added to a solution of 15 methyl 2-aminopent-4-enoate (3.4 g, 26.3 mmol), acetic acid (2.37 g, 39.5 mmol) and benzyl 4 oxopiperidine-1-carboxylate (9.21 g, 39.5 mmol) in dichloroethane (60 mL) at room temperature. After 3 h, the reaction was quenched with saturated aqueous sodium bicarbonate, extracted with methylene chloride (3x), dried over sodium sulfate, filtered and evaporated to give the crude product. This was purified by chromatography (silica gel, 0 to 8% methanol in methylene 20 chloride gradient elution), which gave the title compound (9.42 g). MS 347.2 (M+1). Step B. Benzyl 4-(5-allyl-2,4-dioxoimidazolidin- 1 -yl)piperidine- I -carboxylate Trimethylsilyl isocyanate (1.66 g, 14.4 mmol) was added to a solution of benzyl 4-{ [I -(methoxycarbonyl)but-3-en- I -yl]amino } piperidine- 1 -carboxylate (2.00 g, 5.77 mmol) and 25 DMAP (71 mg, 0.57 mmol) in THF (30 mL) at room temperature. The reaction was heated at 50 oC for 48 h. The reaction was quenched with saturated aqueous sodium bicarbonate, extracted with methylene chloride (3x), dried over sodium sulfate, filtered and evaporated to give the crude product. The crude product was purified by chromatography (silica gel, 0 to 20% methanol in methylene chloride gradient elution), which gave the title compound (1.66 g). MS 358.2 (M + 1). - 69 - WO 2004/092166 PCT/US2004/010851 Step C. Benzyl 4-(6-oxo-6,7-dihydro-5H-imidazo[4,5-clpyridazin-5-yl)piperidine- I -carboxylate Benzyl 4-(5-allyl-2,4-dioxoimidazolidin- 1 -yl)piperidine- 1-carboxylate (0.480 g, 1.34 mmol) was dissolved in THF (5 mL), and osmium tetroxide (0.05 mL, 2.5% solution in t 5 butanol) was added followed by a solution of sodium periodate (0.862 g, 4.03 mmol) in water (4 mL). After 24 h, the reaction was diluted with saturated aqueous Na 2

SO

3 and NaHCO 3 and extracted with ethyl acetate (4x). The combined organic washes were dried over sodium sulfate, filtered and evaporated to give the crude aldehyde (0.352 g). To a portion of this material (0.250 g, 0.696 mmol) in acetic acid (10 mL) was added hydrazine (0.446 mL, 13.9 mmol). This 10 mixture was heated at 50 "C for 24 h, and then concentrated to dryness. Purification by reverse phase HPLC (C-18, 95% water/ acetonitrile -> 5% water/ acetonitrile with 0.1% trifluoroacetic acid) gave the product (0.032 g). MS 354.2 (M + 1). Step D. 5-Piperidin-4-yl-5,7-dihydro-6H-imidazo[4,5-c pyridazin-6-one 15 A solution of benzyl 4-(6-oxo-6,7-dihydro-5H-imidazo[4,5-c]pyridazin-5 yl)piperidine-1-carboxylate (35 mg, 0.099 mmol) and 10% Pd/C (50 mg) in EtOH (5 mL), was hydrogenated under a balloon overnight. The reaction was filtered through Celite with more EtOH and concentrated to afford the title compound (26 mg). MS 220.2 (M+1). 20 INTERMEDIATE 8

OCH

3 N 2 HCI -HN N NH 0 5- Methoxy-2-oxo- 1-(4-piperidinyl)-2,3-dihydro- IH-imidazo[4,5-blpyridine dihydrochloride Step A. 2-Amino-6-chloro-3-nitropyridine A solution of ammonium hydroxide (6.6 g, 0.124 mol) and sodium hydroxide (4.8 25 g, 0.120 mol) in water (45 mL) was added to 2,6-dichloro-3-nitropyridine (12.0 g, 0.62 mol) in ethanol (240 mL). The reaction was refluxed for 2 h, cooled to room temperature and filtered. The pale yellow solid was dried overnight to give the title compound. IH NMR (500 MHz, CDCl3) 8 8.87 (d, J=9 Hz, 1H), 7.8 (br s, 1H), 6.73 (d, J=9 Hz, IH), 5.9 (br s, IH). - 70 - WO 2004/092166 PCT/US2004/010851 Step B. 2-Amino-6-methoxy-3-nitropyridine Sodium metal (0.5 g, 21.7 mmol) was added portion wise to anhydrous methanol 30 mL) under argon. When the sodium was consumed, 1-amino-6-chloro-3-nitropyridine (3.0 g, 17.2 mmol) and methanol (30 mL) were added, and the suspension refluxed for 2 h. The 5 reaction was cooled to room temperature and stirred for 3 h. The yellow solid was filtered and air dried to give the title compound. MS 170 (M+1) 1H NMR (500 MHz, CDCI3) 8 8.29 (d, J=9 Hz, 1H), 7.8 (br s, 1H), 6.14 (d, J=9 Hz, 1H), 5.6 (br s, 1H). Step C. 2,3-Diamino-6-methoxypyridine 10 2-Amino-6-methoxy-3-nitropyridine (2.8 g, 16.5 mmol) was dissolved in warm 1:1 methanol/ethanol (200 mL). The solution was cooled, purged with argon, and 10% palladium on carbon was added (0.45 g). Hydrogen was introduced (1 atm) and the reaction stirred until complete. The catalyst was filtered and the solvent evaporated from the filtrate to give the title compound. MS 140 (M+1) 1H NMR (500 MHz, CDC13) 8 6.93 (d, J=8 Hz, 1H), 15 6.04 (d, J=8 Hz, IH), 4.15(br s, 2H), 3.80 (s, 3H), 3.0 (br s, 2H). Step D. 2-Amino-3-[(1 -t-butoxycarbonylpiperidin-4-yl)amino)-6-methoxypyridine Sodium triacetoxyborohydride (3.39 g, 16.0 mmol) was added to a solution of 2,3-diamino-6-methoxypyridine (2.23 g, 16.0 mmol) and N-(t-butoxycarbonyl)-4-piperidone 20 (7.66 g, 38.4 mmol) in dichloroethane (50 mL) at room temperature. The reaction was quenched with water (50 mL) and stirred overnight, then extracted with chloroform and washed with 5% aqueous sodium hydroxide, water and saturated sodium chloride solution. After drying over sodium sulfate, the solution was filtered and evaporated to give the crude product. This was purified by chromatography, where the more polar product was isolated (silica gel, 50% ethyl 25 acetate hexane, Rf = 0.36), to give the title compound. MS 323 (M+1). 1H NMR (500 MHz, CDCl3) 6 7.99 (d, J-8 Hz, 1H), 6.05 (d, J=8 Hz, 1H), 4.45 (br s), 4.03 (br s), 3.83 (s, 3H), 3.15 (m, IH), 2.86 (m, 2H), 1.91 (d, J=12 Hz, 2H), 1.5 (br s, 11H), 1.26 (br s, 2H). Step E. 5-Methoxy-2-oxo-1-(1-t-butoxvcarbonylpiperidin-4-yl)-2,3-dihydro-1H-imidazo[4,5 30 blpyridine Carbonyldiimidazole (1.6 g, 9.8 mmol) was added to a solution of 2-amino-3-[(1 t-butoxycarbonylpiperidin-4-yl)amino]-6-methoxypyridine (1.29 g, 4.00 mmol) in acetonitrile (100 mL) at room temperature. The reaction was stirred until all the starting material was consumed. Methanol was added to the reaction and the solution stirred for several hours, then - 71 - WO 2004/092166 PCT/US2004/010851 the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate, washed with water and saturated brine, and then dried over magnesium sulfate. The crude product was purified by chromatography (silica gel, 2.5% to 5% methanol in methylene chloride gradient elution), which gave the title compound. MS 349 (M+1) IH NMR (500 MHz, CDCI3) 8 8.50 (br 5 s, 1H), 7.29 (d, J=8 Hz, IH), 6.43 (d, J=8 Hz, 1H), 4.46 (m, 1H), 4.31 (br s, 2H), 3.90 (s, 3H), 2.85 (br s, 2H), 2.13 (m, 2H), 1.85 (d, J=12 Hz, 2H), 1.50 (s, 9H). Step F. 5-Methoxy-2-oxo- 1 -(4-piperidinyl)-2,3-dihydro- 1 H-imidazo[4,5-blpyridine 5-Methoxy-2-oxo-1-(1-t-butoxycarbonylpiperidin-4-yl)-2,3-dihydro-1H 10 imidazo[4,5-b]pyridine (100 mg, 0.287 mmol) was dissolved in methanol (2.5 mL) and a solution of 2N hydrochloric acid in ether (3 mL) was added at room temperature. After 2 h, the volatiles were removed in vacuo, to give the title compound (61 mg). MS 249.1 (M + 1). 15 INTERMEDIATE 9 F N 2 HCI HN N NH 0 4-Fluoro-2-oxo- 1-(4-piperidinyl)-2,3-dihydro-1H-imidazof4,5-blpyridine Step A. N-(5-Fluoropyridin-2-yl)-2,2-dimethylpropanamide 20 To a 0 'C solution of 2-amino-5-fluoropyridine (1.00 g, 8.92 mmol) and triethylamine (1.35 g, 13.4 mmol) in dichloromethane (30 mL) was added trimethylacetyl chloride (1.29 g, 10.7 mmol) and DMAP (0.11 g, 0.89 mmol). The solution was allowed to warm to room temperature. After 4 h, saturated aqueous NaHCO 3 was added, the layers separated and the aqueous phase backwashed with DCM. The combined organics were dried over magnesium 25 sulfate, filtered and concentrated and the residue purified by silica gel chromatography (5% - 40% EtOAc / hexanes) to give the title compound (1.34 g). MS 197.3 (M+1). Step B. N-(3-Azido-5-fluoropyridin-2-yl)-2,2-dimethylpropanamide - 72 - WO 2004/092166 PCT/US2004/010851 To a -78 'C solution of N-(5-fluoropyridin-2-yl)-2,2-dimethylpropanamide (1.34 g, 6.83 mmol) in tetrahydrofuran (25 mL) was added tert-butyllithium (1.31 mL of a 1.7 M solution, 20.5 mmol) drop wise. After 3 h at -78 'C, 4-dodecylbenzenesulfonyl azide (3.60 g, 10.2 mmol) was added at the reaction was allowed to warm to room temperature. After I h, saturated 5 aqueous NH 4 CI was added, and the tetrahydrofuran was removed via rotary evaporator. Dichloromethane was added, the layers separated and the aqueous phase backwashed with DCM. The combined organics were dried over magnesium sulfate, filtered and concentrated and the residue purified by two successive silica gel chromatographies (10% -> 80% EtOAc / hexanes, then 5% -> 42% EtOAc / hexanes) to give the title compound (0.275 g). MS 234.0 (M+1). 10 Step C. 3-Azido-5-fluoropyridin-2-amine N-(3-Azido-5-fluoropyridin-2-yl)-2,2-dimethylpropanamide (275 mg, 1.16 mmol) in 3 N HCI (5 mL) was heated to 100 'C. After 2 h, the volatiles were removed in vacuo, to give the title compound as its HCl salt (180 mg). MS 154.2 (M + 1). 15 Step D. 5-Fluoropyridine-2,3-diamine The HCI salt of 3-azido-5-fluoropyridin-2-amine (1.90 g, 10.0 mmol) was dissolved in tetrahydrofuran (100 mL) and treated with MP-Carbonate (Argonaut, 11.5 g). After 1 h, the mixture was filtered, rinsed with more tetrahydrofuran, and concentrated. This residue 20 was dissolved in ethanol (50 mL), purged with argon, and 10% palladium on carbon was added (0.15 g). Hydrogen was introduced (1 atm) and the reaction stirred until complete. The catalyst was filtered and the solvent evaporated from the filtrate to give the title compound (1.18 g). MS 128.0 (M+1) 25 Step E. tert-Butyl 4- r(2-amino-5-fluoropyridin-3 -vl)aminolpiperidine- I -carboxylate Sodium triacetoxyborohydride (2.95 g, 13.9 mmol) was added to a solution of 5 fluoropyridine-2,3-diamine (1.18 g, 9.28 mmol), acetic acid (0.56 g, 9.28 mmol) and I-(t butoxycarbonyl)-4-piperidone (1.85 g, 9.28 mmol) in 1,2-dichloroethane (20 mL) at room temperature. After Ih, the reaction was quenched with water (20 mL) and extracted with 30 dichloromethane. After drying over sodium sulfate, the solution was filtered and evaporated to give the crude product. This was purified by chromatography, (silica gel, 5% --) 15% MeOH / DCM; then C-18, 95% water/ acetonitrile --- 5% water/ acetonitrile with 0.1% trifluoroacetic acid) to give the title compound (0.73 g). MS 311.2 (M+1). - 73 - WO 2004/092166 PCT/US2004/010851 Step F. tert-Butyl 4-(6-fluoro-2-oxo-2,3-dihydro-1H-imi dazo[4,5-blpyridin- 1 -Vl)piperidine- 1 carboxylate Carbonyldiimidazole (1.53 g, 9.41 mmol) was added to a solution of tert-butyl 4 [(2-amino-5-fluoropyridin-3-yl)amino]piperidine-1-carboxylate (0.73 g, 2.35 mmol) in 5 acetonitrile (10 mL) at room temperature. The reaction was stirred until all the starting material was consumed (approximately 2 h) and then the solvent was evaporated in vacuo. The residue was diluted with water, extracted with dichloromethane (3 x), dried over magnesium sulfate and then concentrated. The crude product was purified by chromatography (silica gel, 1% to 10% methanol in methylene chloride gradient elution), which gave the title compound (0.309 g). MS 10 337.2 (M+1) Step G. 4-Fluoro-2-oxo-1-(4-piperidinyl)-2,3-dihydro-IH-imidazo[4,5-blpyridine tert-Butyl 4-(6-fluoro-2-oxo-2,3-dihydro- 1 H-imidazo[4,5-b]pyridin- 1 yl)piperidine-1-carboxylate (340 mg, 1.01 mmol) was dissolved in dichloromethane (5 mL) and 15 trifluoroacetic acid (5 mL) was added. After 2h, the reation was concentrated, diluted with dichlormethane (5 mL) and a solution of IN hydrochloric acid in 1,4-dioxane (2 mL) was added at room temperature. Concentration afforded the title compound (302 mg). MS 237.2 (M + 1) 1 H NMR (500 MHz, CDOD13) 8 7.92 (br s, 1H), 7.70 (dd, 1H), 4.60 (m, 1H), 3.60 (s, 2H), 3.25 (dd, 2H), 2.70 (m, 2H), 2.10 (d, 2H). 20 INTERMEDIATE 10 -N H N N /-NH 25 3-Piperidin-4-yl-3,4-dihydropyrido[4,3-dlpyrimidin-2(1H)-one Step A. Ethyl 4-[({4-[(tert-butoxycarbonyl)aminolpyridin-3-yl methyl)aminolpiperidine-1 carboxylate Sodium triacetoxyborohydride (1.70 g, 8.03 mmol) and acetic acid (0.29, 4.82 mmol) were added to a solution of N-Boc-4-amino-3-pyridine carboxaldehyde (0.36 g, 1.61 30 mmol) and ethyl 4-aminopiperidine-1-carboxylate (0.33 g, 1.93 mmol) in dichloroethane (5 mL) at room temperature. The reaction was stirred overnight, and quenched with saturated aqueous -74- WO 2004/092166 PCT/US2004/010851 sodium bicarbonate. This was separated, extracted with ethyl acetate and the combined organics were dried over sodium sulfate. The solution was filtered and evaporated to give the crude product. This was purified by chromatography (silica gel, 0 to 12% methanol in methylene chloride gradient elution), which gave the title compound (0.24 g). MS 379.2. 5 Step B. Ethyl 4-(2-oxo- 1,4-dihydropyrido[4,3-dlpyrimidin-3(2H)-yl)piperidine-1 -carboxylate Trifluoroacetic acid (0.50 mL) was a add to a solution of the material from Step A (0.24g, 0.63 mmol) in dichloromethane (5 mL). After stirring overnight, another 0.5 mL of trifluoroacetic acid was added. After an additional 2h, the reaction was concentrated. This 10 material was dissolved in acetonitrile (5 mL) and carbonyldiimidazole (0.31 g, 1.89 mmol) was added at room temperature. After 2 h, the acetonitrile was evaporated in vacuo, the residue partitioned between iN NaOH and dichloromethane, and the organic phase dried over magnesium sulfate. The crude product was purified by chromatography (silica gel, 10 to 15% methanol in methylene chloride gradient elution), which gave the title compound (0.089 g). MS 15 305.3. Step C. 3 -Piperidin-4-yl-3,4-dihydropyiido[4,3-dlpyrimidin-2(lH)-one Ethyl 4-(2-oxo-1, 4 -dihydropyrido[4,3-d]pyrimidin-3(2H)-yl)piperidine-1 carboxylate (0.089 g, 0.29 mmol) was diluted in IN NaOH (5 mL) and heated to reflux. After 4 20 h, the reaction was concentrated in vacuo, the residue was diluted with MeOH: DCM, filtered and concentrated. The crude material was purified by reverse phase HPLC (C-18, 5% to 95% 0.1% trifluoroacetic acid/acetonitrile in 0.1% aqueous trifluoroacetic acid gradient elution) to give TFA salt of the title compound (0.12 g). MS 233.3 (M + 1). 25 . INTERMEDIATE 11 HN N N )N H 3-Piperidin-4-yl-3,4-dihydropyridor3,4-dlpyrimidin-2(iH)-one Step A. Ethyl 4-[({3- [(tert-butoxvcarbonyl)amino1pyridin-4-yl I methyl)aminolpiperidine-1 30 carboxylate -75- WO 2004/092166 PCT/US2004/010851 Sodium triacetoxyborohydride (0.57 g, 2.70 mmol) and acetic acid (0.41, 6.75 mmol) were added to a solution of N-Boc-3-amino-4-pyidine carboxaldehyde (0.50 g, 2.25 mmol) and ethyl 4-aminopiperidine-1-carboxylate (0.47 g, 2.70 mmol) in dichloroethane (5 nL) at room temperature. The reaction was stirred overnight, and quenched with saturated aqueous 5 sodium bicarbonate. This was separated, extracted with ethyl acetate and the combined organics were dried over sodium sulfate. The solution was filtered and evaporated to give the crude product. This was purified by chromatography (silica gel, I to 12% methanol in methylene chloride gradient elution), which gave the title compound (0.47 g). MS 379.3. 10 Step B. Ethyl 4-(2-oxo- 1,4-dihydropyrido[3,4-dlpyrimidin-3(2H)-yl)piperidine- 1 -carboxyl ate Trifluoroacetic acid (1.43 g) was added to a solution of the material from Step A (0.47 g, 1.24 mmol) in dichloromethane (10 mL). After stirring overnight, the reaction was concentrated. This material was dissolved in acetonitrile (5 mL) and carbonyldiimidazole (0.62 g, 3.73 mmol) was added at room temperature. After 2 d, the acetonitrile was evaporated in 15 vacuo, the residue partitioned between IN NaOH and dichloromethane, and the organic phase dried over magnesium sulfate. The crude product was purified by chromatography (silica gel, I to 20% methanol in methylene chloride gradient elution), which gave the title compound (0.15 g). MS 305.2. 20 Step C. 3-Piperidin-4-yl-3,4-dihydropyridof3,4-dlpyrimidin-2(1H)-one Ethyl 4-(2-oxo-1,4-dihydropyrido[3,4-d]pyrimidin-3(2H)-y)piperidine-1 carboxylate (0.15 g, 0.48 mmol) was diluted in IN NaOH (10 mL) and heated to reflux. After 5 h, the reaction was concentrated in vacuo, the residue was diluted with MeOH: DCM, filtered and concentrated. The crude material was purified by reverse phase HPLC (C-18, 5% to 95% 25 0.1% trifluoroacetic acid/acetonitrile in 0.1% aqueous trifluoroacetic acid gradient elution) to give TFA salt of the title compound (0.17 g). MS 233.3 (M + 1). INTERMEDIATE 12 HN N NHN 30 - 76 - WO 2004/092166 PCT/US2004/010851 3-Piperidin-4-yI-3,4-dihydropyridof2,3-dlpyrimidin-2(1H)-one Step A. 2-[(2,4-Dimethoxybenzyl)aminolnicotinonitrile 2,4-Dimethoxybenzylamine (2.90 g, 17.3 mmol) and triethylamine (1.75 g, 17.3 mmol) were added sequentially to a solution of 2-chloronicotinonitrile (2.0 g, 14.4 mmol) in 5 NN-dimethylacetamide (29 mL). The reaction was heated at 800C for 4 h, quenched with water and extracted with diethyl ether (3x). The combined organic extracts were washed water, saturated brine, dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography (silica gel, 0-5% ethyl acetate (with 0.1 triethylamine) in dichloromethane gradient elution) to produce the title compound (2.80 g). MS 270.3 (M + 1). 10 Step B. 3-(Aminomethyl)-N-(2,4-dimethoxybenzyl)pvridin-2-amine Lithium aluminum hydride (1.0 M in THF, 11.4 mL, 11.4 mmol) was added slowly to a solution of 2-[(2,4-dimethoxybenzyl)amino]nicotinonitrile (2.80 g, 10.4 mmol) in tetrahydrofuran (35 mL) at 0 OC. The reaction was allowed to warm to room temperature and 15 stir for 4 h. The reaction was carefully quenched with a saturated aqueous solution of sodium sulfate, filtered with copious dichloromethane and concentrated to produce the title compound (2.92 g). MS 274.3 (M+1). Step C. tert-Butyl 4-[({2-[(2,4-dimethoxybenzyllaminolpyridin-3-yl methyl)aminolpiperidine-1 20 carboxylate Sodium triacetoxyborohydride (0.78 g, 3.66 mmol) and acetic acid (0.22 g, 3.66 mmol) were added to a solution of a portion of the material form Step B (1.00 g, <3.66 mmol) and N-(t-butoxycarbonyl)-4-piperidone (0.73 g, 3.66 mmol) in dichloroethane (20 mL) at room temperature. After 3 h, the reaction was washed with saturated aqueous sodium bicarbonate, 25 dried over sodium sulfate, the solution was filtered and evaporated to give the product (1.83 g). MS 457.3 (M+1). Step D. tert-Butyl 4- [1-(2,4-dimethoxybenzyl)-2-oxo- 1,4-dihydropyrido[2,3-dlpyrimidin-3 (2H) yllpiperidine- 1 -carboxylate 30 Carbonyldiimidazole (0.65 g, 4.0 mmol) was added to a solution of the material from Step C in dimethylformamide (20 mL) and the reaction was heated to 150 oC. After I d, further carbonyldiimidazole (0.65 g, 4.0 mmol) was added and the reaction heated for an additional 3 h. The reaction was diluted with water and extracted with dichloromethane, and the organic phase dried over sodium sulfate. The crude product was purified by chromatography - 77 - WO 2004/092166 PCT/US2004/010851 (silica gel, 20 to 80% ethyl acetate in methylene chloride gradient elution), which gave the title compound (0.35 g). MS 483.3 (M+1). Step E. 3-Piperidin-4-yl-3,4-dihydropyrido[2,3-dlpyrimidin-2(1H)-one 5 tert-Butyl 4- [1- (2,4-dimethoxybenzyl)-2-oxo- 1,4-dihydropyri do[2,3-d]pyrimidin 3(2H)-yI]piperidine-1-carboxylate (0.21 g, 0.43 mmol) was dissolved in trifluoroacetic acid (5 mL) and stirred overnight. The reaction was then heated to 50 OC for 3 h and concentrated to afford the bisTFA salt of the title compound (0.11 g). MS 233.3 (M+1). -78- WO 2004/092166 PCT/US2004/010851 INTERMEDIATE 13

N

H N N -NH 5 3-Piperidin-4-yl-3,4-dihydropyrido[3,2-dipyrimidin-2(1H)-one Step A. 3-[(2,4-Dimethoxybenzyl)aminolpyridine-2-carbonitrile 2,4-Dimethoxybenzylamine (3.29 g, 19.7 mmol) and triethylamine (1.99 g, 19.7 mmol) were added sequentially to a solution of 2-cyano-3-fluoropyridine (2.0 g, 16.4 mmol) (Sakamoto et. al., Chem. Pharm. Bull., 1985, 33, 565-71) in NN-dimethylacetamide (29 mL). 10 The reaction was heated at 80 0 C for 4 h, quenched with water and extracted with diethyl ether (3x). The combined organic extracts were washed water, saturated brine, dried over magnesium sulfate and concentrated. The crude product was purified by flash chromatography (silica gel, 0 12% ethyl acetate (with 0.1 triethylamine) in dichloromethane gradient elution) to produce the title compound (3.25 g). MS 270.3 (M + 1). 15 Step B. 2-(Aminomethyl)-N-(2,4-dimethoxybenzyl)pyridin-3-amine Lithium aluminum hydride (1.0 M in THF, 13.3 mL, 13.3 mmol) was added slowly to a solution of 3-[(2,4-dimethoxybenzyl)amino]pyridine-2-carbonitrile (3.25 g, 12.1 mmol) in tetrahydrofuran (40 mL) at 0 OC. The reaction was warmed to room temperature and 20 stirred for 4 h. The reaction was carefully quenched with a saturated aqueous solution of sodium sulfate, filtered with copious dichloromethane and concentrated to produce the title compound (2.68 g). MS 274.3 (M + 1). Step C. tert-Butyl 4-[({3-[(2,4-dimethoxybenzyl)aminolpyridin-2-yl methyl)aminol1piperidine-1 25 carboxylate Sodium triacetoxyborohydride (1.16 g, 5.49 mmol) and acetic acid (0.22 g, 3.66 mmol) were added to a solution of a portion of the material form Step B (1.72 g, 3.66 mmol) and N-(t-butoxycarbonyl)-4-piperidone (0.88 g, 4.39 mmol) in dichloroethane (20 mL) at room temperature. After 3 h, the reaction was washed with saturated aqueous sodium bicarbonate, 30 dried over sodium sulfate, the solution was filtered and evaporated to give the product (1.72 g). MS 457.3 (M+1). -79- WO 2004/092166 PCT/US2004/010851 Step D. tert-Butyl 4-[1-(2,4-dimethoxybenzyl)-2-oxo- I4-dihydropyrido[3,2-dpyrimidin-3(2H) yllpiperidine- 1-carboxylate Carbonyldiimidazole (1.22 g, 7.53 mmol) was added to a solution of the material 5 from Step C in dimethylformamide (20 mL) and the reaction was heated to 150 OC overnight. The reaction was diluted with water and extracted with dichloromethane, and the organic phase dried over sodium sulfate. The crude product was purified by chromatography (silica gel, 30 to 100% ethyl acetate in methylene chloride gradient elution), which gave the title compound (0.10 g). MS 483.3 (M+1). 10 Step E. 3-Piperidin-4-yl-3,4-dihydropyrido[3,2-dlpyrimidin-2(IH)-one tert-Butyl 4-[1-(2,4-dimethoxybenzyl)-2-oxo-1,4-dihydropyrido[3,2-d]pyrimidin 3(21)-yl]piperidine-1-carboxylate (0.10 g, 0.21 mmol) was dissolved in trifluoroacetic acid (5 mL) and stirred overnight. The reaction was concentrated to afford the bis-TFA salt of the title 15 compound (0.048 g). MS 233.2 (M+1). INTERMEDIATE 14 MeO 0 N

"NH

2 20 (3R,6S)-3-Amino- I -(2-methoxyethyl)-6-phenylazepan-2-one Step A: 2-Bromo-N-(2,4-dimethoxybenzyl)prop-2-en-1-amine Triethylamine (16.0 mL, 114 mmol) was added to a solution of 2,4 dimethoxybenzylamine hydrochloride (11.1 g, 54.5 mmol) and 2,3-dibromopropene (10.9 g, 54.5 25 mmol) in dichloromethane (200 mL). After 18 h, water was added and the mixture was extracted with dichloromethane (3x). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography [100% dichloromethane -+ 95% dichloromethane/ 5% (10% ammonium hydroxide/ methanol)] gave the title compound (7.85 g). - 80 - WO 2004/092166 PCT/US2004/010851 Step B: Benzyl (1R)- 1- r(2-bromoprop-2-enyl)(2,4-dimethoxybenzyl) aminolcarbonyl Ibut-3 enylcarbamate 1-[3-(Dimethylamino)propyll-3-ethylcarbodiimide hydrochloride (55 mg, 0.285 5 mmol) was added to a solution of 2-bromo-N-(2,4-dimethoxybenzyl)prop-2-en-1-amine (73 mg, 0.256 mmol) and (2R)-2-{[(benzyloxy)carbonyl]amino}pent-4-enoic acid (71 mg, 0.285 mmol) in dichloromethane (5 mL). After 18 h the mixture was concentrated. Purification by silica gel chromatography (5% ethyl acetate/ hexanes -> 30% ethyl acetate/ hexanes) gave the title compound (77 mg). MS 517 (M+1). 10 Step C: Benzyl (IR)-1-I [(2,4-dimethoxybenzyl)(2-phenylprop-2-enyl)aminolcarbonyl Ibut-3 enylcarbamate Tetrakis(triphenylphosphine)palladium(0) (1.11 g, 0.962 mmol) was added to a solution of benzyl (1R)-1-{ [(2-bromoprop-2-enyl)(2,4-dimethoxybenzyl) amino]carbonyl }but-3 15 enylcarbamate (2.49 g, 4.81 mmol), phenylboronic acid (0.65 g, 5.29 mmol) and sodium carbonate (2M in water; 4.81 mL, 9.63 mmol) in tetrahydrofuran (54 mL) and water (20 mL), and the mixture heated to 60 'C. After 1 h, the mixture was allowed to cool to ambient temperature and extracted with dichloromethane (3x). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. 20 Purification by silica gel chromatography (5% ethyl acetate/ hexanes -> 30% ethyl acetate/ hexanes) gave the title compound (2.02 g). MS 515 (M+1). Step D: Benzyl (3R)-I-(2,4-dimethoxybenzyl)-2-oxo-6-phenyl-2,3,4,7-tetrahydro-1H-azepin-3 ylcarbamate 25 [1,3-bis-(2,4,6-trimethylphenyl-2-imidazolidinylidene)dichloro(phenylmethylene) -(tricyclohexylphosphine)ruthenium] (Grubbs second generation catalyst) (0.68 g, 0.79 mmol) was added to a solution of benzyl (1R)-1-{ [(2,4-dimethoxybenzyl)(2-phenylprop-2 enyl)amino]carbonyl}but-3-enylcarbamate (2.02 g, 3.93 mmol) in dichloromethane (395 mL) and heated to 40 *C. After 40 h, the mixture was allowed to cool to ambient temperature and 30 concentrated. Purification by silica gel chromatography (5% ethyl acetate/ hexanes -+ 30% ethyl acetate/ hexanes) gave the title compound (1.00 g). MS 487 (M+1). 'H NMR (500 MHz, CDCl 3 ) 8 7.39-7.31 (m, 5H), 7.26-7.19 (m, 3H), 7.17 (d, J = 8.3 Hz, IH), 6.99 (d, J = 7.1 Hz, 2H), 6.41 (dd, J = 8.3, 2.0 Hz, 1H), 6.33 (s, 1H), 6.22 (d, J = 6.4 Hz, 1H), 5.77-5.76 (m, 1H), 5.16-5.09 (m, - 81 - WO 2004/092166 PCT/US2004/010851 3H), 4.82 (d, J = 14.7 Hz, 1H), 4.65 (dd, J = 17.6, 2.7 Hz, 1H), 4.54 (d, J = 14.4 Hz, IH), 3.93 (d, J = 17.6 Hz, 1H), 3.77 (s, 3H), 3.64 (s, 3H), 2.91-2.86 (m, 1H), 2.42-2.36 (m, 1H). Step E: Benzyl (3R)-2-oxo-6-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-ylcarbamate 5 A solution of L-methionine (2.56 g, 17.2 mmol) in trifluoroacetic acid (15 mL) was added to a solution of benzyl (3R)-1-(2,4-dimethoxybenzyl)-2-oxo-6-phenyl-2,3,4,7 tetrahydro-IH-azepin-3-ylcarbamate (0.84 g, 1.72 mmol) in dichloromethane (20 mL). After 18 h, the mixture was concentrated and water was added. The mixture was extracted with ethyl acetate, washed with water (2x), saturated aqueous sodium bicarbonate (2x), saturated brine, 10 dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (5% ethyl acetate/ hexanes -+ 50% ethyl acetate/ hexanes) gave the title compound (0.44 g). MS 337 (M+1). Step F: tert-Butyl (3R,6S)-2-oxo-6-phenylazepan-3-ylcarbamate 15 10% Palladium on carbon (75 mg) was added to a solution of benzyl (3R)-2-oxo 6-phenyl-2,3,4,7-tetrahydro-IH-azepin-3-ylcarbamate (596 mg, 1.77 mmol) and di-tert-butyl dicarbonate (773 mg, 3.54 mmol) in ethyl acetate (30 mL). The reaction vessel is evacuated and back-filled with nitrogen (3x), then back-filled with hydrogen (1 atm). After 2 h, the mixture was filtered and concentrated. Purification by silica gel chromatography (30% ethyl acetate/ 20 hexanes -* 50% ethyl acetate/ hexanes) gave the title compound (289 mg). Step G: tert-Butyl (3R,6S)-1-(2-methoxyethyl)-2-oxo-6-phenylazepan-3-vlcarbamate Sodium hydride (60% dispersion in mineral oil; 6.2 mg, 0.158 mmol) was added to a solution of tert-butyl (3R,6R)-2-oxo-6-phenylazepan-3-ylcarbamate (40 mg, 0.131 mmol) 25 and 2-bromoethyl methyl ether (0.013 mL, 0.138 mmol) in NN-dimethylformamide (2 mL) at 0 'C. After addition, the mixture was allowed to warm to ambient temperature. After 4 h, the reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was washed with water (3x), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (5% ethyl acetate/ hexanes -> 30% ethyl 30 acetate/ hexanes) gave the title compound (41 mg). MS 363 (M+1). Step H: (3R,6S)-3-Amino-1-(2-methoxyethyl)-6-phenylazepan-2-one Trifluoroacetic acid (2.5 mL) was added to a solution of tert-butyl (3R,6S)-1-(2 methoxyethyl)-2-oxo-6-phenylazepan-3-ylcarbamate (41 mg, 0.113 mmol) in dichloromethane (5 - 82 - WO 2004/092166 PCT/US2004/010851 mL). After I h, the solution was concentrated. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with dichloromethane (3x). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. MS 263 (M+1). 'H NMR (500 MHz, CDC 3 ) 8 7.32 (t, J = 7.3 Hz, 2H), 7.25-7.22 5 (m, 1H), 7.18 (d, J = 8.3 Hz, 2H), 3.83-3.76 (m, 3H), 3.56-3.49 (m, 3H), 3.35 (s, 3H), 3.34-3.30 (m, 1H), 2.77-2.72 (m, 1H1), 2.13-2.10 (m, 1H), 2.03-1.94 (m, 2H), 1.74-1.68 (m, 1H). Essentially following the procedures outlined for the preparation of Intermediate 14, the Intermediates in Table I-1 were prepared. 10 TABLE I-1 R, 0 N 3 "NH 2 6 Intermediate C-3 C-6 RI MS (M+1) 15 R S H 205 16 R R H 205 17 R S CH 3 219 18 R S CH 2

CH

3 233 19 R S CH 2

CF

3 287 20 R S CH 2

CO

2

CH

3 277 21 R S (CH 2

)

2 0CH 2

CH

3 277 22 R S CH 2 CN 244 23 R S >-CH 2 259 - 83 - WO 2004/092166 PCT/US2004/010851 24 R S C 291.1 25 R S CH 2

CH

2 F 251.1 26 R S CH 2

CHF

2 269.1 27 R S CH 2

CHCF

2 281 28 R S O -CH2 295 29 R S O CH2 296 30 R S H2C O 289 31 R S 289 0 CH 2 32 R S CH2 291 33 R S CH2 277 34 R S _s\ CH9 279 35 R S O 311 CH, 36 R S (CH 2

)

2 0CF 3 317 37 R S O CH, 289 -84- WO 2004/092166 PCT/US2004/010851 38 R S HO CH2 263.2 39 R S O C H, 289 40 R S HO 317.1

CH

2

F

3 C 41 R S Ph 281 42 R S 277.2

CH

2 _______ HO _____ INTERMEDIATE 43 H O N

."NH

2 HO 5 (3R)-3-Amino-6-(4-hydroxyphenyl)azepan-2-one Step A: Benzyl (3R)-6-bromo-1-(2,4-dimethoxybenzyl)-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3 ylcarbamate [1,3-bis-(2,4,6-trimethylphenyl-2-i midazolidinylidene)dichloro(phenylmethylene) 10 -(tricyclohexylphosphine)ruthenium] (Grubbs second generation catalyst) (1.78 g, 2.05 mmol) was added to a solution of benzyl (1R)-1-{ [(2-bromoprop-2-enyl)(2,4-dimethoxybenzyl) amino]carbonyl }but-3-enylcarbamate (5.29 g, 10.2 mmol) in dichloromethane (1000 mL) and heated to 40 'C. After 18 h, the mixture was allowed to cool to ambient temperature and concentrated. Purification by silica gel chromatography (5% ethyl acetate/ hexanes -+ 30% ethyl 15 acetate/ hexanes) gave the title compound (0.79 g). MS 489 (M+1). 'H NMR (500 MHz, CDC 3 ) 6 7.36-7.35 (m, 4H), 7.33-7.30 (m, JH), 7.17-7.15 (m, 1H), 6.46-6.43 (m, 2H), 6.13 (d, J = 6.1 Hz, IH), 6.04-6.03 (m, 1H), 5.13-5.07 (m, 2H), 4.93-4.88 (m, 1H), 4.75 (d, J = 14.4 Hz, 1H), - 85 - WO 2004/092166 PCT/US2004/010851 4.64-4.60 (m, 1H), 4.47 (d, J = 14.4 Hz, IH), 3.86 (d, J = 18.3 Hz, 1H), 3.81 (s, 3H), 3.80 (s, 3H), 2.68-2.63 (m, 1H), 2.24-2.05 (m,1H). Step B: Benzyl (3R)-6-bromo-2-oxo-2,3,4,7-tetrahydro-IH-azepin-3-ylcarbamate 5 A solution of L-methionine (274 mg, 1.84 mmol) in trifluoroacetic acid (5 mL) was added to a solution of benzyl (3R)-6-bromo-1-(2,4-dimethoxybenzyl)-2-oxo-2,3,4,7 tetrahydro-IH-azepin-3-ylcarbamate (90 mg, 0.184 mmol) in dichloromethane (5 mL). After 18 h, the mixture was concentrated. Purification by reverse phase HPLC (C-18, 95% water/ acetonitrile -> 5% water/ acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (17 10 mg). MS 339 (M+1). Step C: Benzyl (3R)-6-(4-hydroxyphenyl)-2-oxo-2,3,4,7-tetrahydro-IH-azepin-3-ylcarbamate Palladium acetate (1 mg, 0.003 mmol) was added to a solution of benzyl (3R)-6 bromo-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-ylcarbamate (18 mg, 0.053 mmol), 4 15 hydroxyphenylboronic acid (9 mg, 0.064 mmol), sodium carbonate (2M in water; 0.066 mL, 0.133 mmol) and trisodium 3-[bis(3-sulfonatophenyl)phosphino] benzenesulfonate (5 mg, 0.088 mmol) in NN-dimethylformnamide (0.45 mL) and water (0.15 mL) and heated to 80 'C. After 1.5 h, the mixture was allowed to cool to ambient temperature and filtered. Purification by reverse phase HPLC (C-18, 95% water/ acetonitrile -> 5% water/ acetonitrile with 0.1% 20 trifluoroacetic acid) gave the title compound (15 mg). MS 353 (M+1). Step D: (3R)-3-Amino-6-(4-hydroxyphenyl)azepan-2-one 10% Palladium on carbon (10 mg) was added to a solution of benzyl (3R)-6-(4 hydroxyphenyl)-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-ylcarbamate (15 mg, 0.043 mmol) in 25 toluene (5 mL) and methanol (1 mL). The reation vessel is evacuated and back-filled with nitrogen (3x), then back-filled with hydrogen (1 atm). After 18 h, the mixture was filtered and concentrated. MS 221 (M+1). Essentially following the procedures outlined for the preparation of Intermediate 43, the 30 Intermediates in Table 1-2 were prepared. Compounds along the route to the Intermediates in Table 1-2, can be further processed (e.g. alkylation of Ni) according to those skilled in the art following essentially the same procedures as outlined above to afford another set of intermediates. - 86 - WO 2004/092166 PCT/US2004/010851 TABLE 1-2 HO0 N R3 .NH2 Rl6 Intermediate C-3 C-6 RI MS (M+1) 44 R RorS 223.2 45 R RorS 223.2 F 46 R RorS F 223.2 47 R R or S 241.2 F F 48 R R or S 206.3 49 R R or S 206.3 N 50 R R or S 206.2 - 87 - WO 2004/092166 PCT/US2004/010851 51 R R or S F 241.2 F 52 R R or S 241.2 53 R R or S 273.2 ____ __ _ ____CFj 54 R RorS 219.2 CHa 55 R R or S 219.2

CH

3 56 R R or S 219.2

H

3 C INTERMEDIATE 57 5 H O N

""'NH

2 C, Cl (3R)-3-Amino-6-(2,3-dichlorophenyl)azepan-2-one - 88 - WO 2004/092166 PCT/US2004/010851 Step A. Benzyl (5R or S)-N,N-bis(tert-butoxycarbonyl)-5-(2,3-dichlorophenyl)-6-nitro-D norleucinate To a slurry of 1-bromo-2,3-dichlorobenzene (1.46 g, 6.46 mmol) in diethyl ether (10 mL) was added magnesium (0.157 g, 6.46 mmol) and a crystal of iodine. This mixture was refluxed 5 for 3 h, and then cooled to room temperature. A solution of benzyl (2R,5E)-2-[bis(tert butoxycarbonyl)amino]-6-nitrohex-5-enoate (0.50 g, 1.08 mmol) in diethyl ether (10 mL) was cooled to 0 'C, and 2.0 mL of the Grignard solution prepared above was added. After 1 and 2 h, respectively, 2.0 and 1.0 mL of the Grignard solution was added. The reaction was quenched with a saturated aqueous solution of ammonium chloride, the phases separated and the organic 10 phase washed with saturated aqueous sodium potassium tartrate and brine. The combined organics were dried over magnesium sulfate, filtered and concentrated to give a residue that was purified by silica gel chromatography (0% -- 3% methanol / dichloromethane) to give the title compound (0.52 g). MS 411.0 (M+1 - 2Boc). 15 Step B. Benzyl N2,N2-bis(tert-butoxycarbonyl)-5-(2,3-dichlorophenyl)-D-lysinate To an EtOH rinsed (4x5 mL) slurry of Raney Ni (1 mL) was added a solution of benzyl (5R or S)-NN-bis(tert-butoxycarbonyl)-5-(2,3-dichlorophenyl)-6-nitro-D-noreucinate (0.52 g, 0.85 mmol) in EtOH (5 mL). This slurry was hydrogenated under a balloon of hydrogen for 2h. The reaction was filtered through Celite with more EtOH and concentrated to afford the title 20 compound (0.45 g). MS 581 (M+1). Step C. (3R)-3-Amino-6-(2,3-dichlorophenyl)azepan-2-one To a solution benzyl N 2

,N

2 -bis(tert-butoxycarbonyl)-5-(2,3-dichlorophenyl)-D-lysinate (0.45 g, 0.77 mmol) in MeOH (4 mL) and water (2 mL) was added IN NaOH (3.1 mL, 3.1 25 mmol). This solution was heated to 40 'C for 6 h, then neutralized with IN HCI and concentrated. To a solution of this residue in DCM (10 mL) were added EDC (0.19 g, 0.97 mmol) and HOAT (53 mg, 0.39 mmol) followed by triethylamine (0.32 mL, 0.73 mmol). After 2 h, NaHCO 3 was added, the layers separated and the aqueous phase backwashed with DCM. The combined organics were dried over magnesium sulfate, filtered and concentrated. This residue 30 was purified by silica gel chromatography (0.5% -> 10% MeOH/ DCM) to give di-tert-butyl [(3R)-6-(2,3-dichlorophenyl)-2-oxoazepan-3-yl]imidodicarbonate (300 mg). MS 473 (M+1). Standard deprotection of a portion of this material gave the title product. MS 273 (M+1). - 89 - WO 2004/092166 PCT/US2004/010851 Essentially following the procedures outlined for the preparation of Intermediate 57, the Intermediates in Table 1-3 were prepared. Compounds along the route to the Intermediates in Table 1-3, can be further processed (e.g. alkylation of NI) according to those skilled in the art following essentially the same procedures as outlined above to afford another set of 5 intermediates. TABLE 1-3 H O N 3

"NH

2

R

1 6 10 Intermediate C-3 C-6 RI MS (M+1) 58 R R or S 239.1 CI 59 R R or S 439.2 diBoc CI 60 R R or S 211.3 61 R R or S 371.3 diBoc 62 R R or S 219.2 - 90 - WO 2004/092166 PCT/US2004/010851 63 R R or S 257.2 F Cl INTERMEDIATE 64 Nj

N"'NH

2 5 (2S,6R)-6-Amino-4-(cyclopropylmethyl)-2-phenyl-1,4-oxazepan-5-one Step A. tert-Butyl cyclopropylmethyl [(2S)-2-hydroxy-2-phenyl ethyllcarbamate (S)-Styrene oxide (4.83 g, 40.3 mmol) and cyclopropanemethylamine (4.00 g, 56.4 mmol) were dissolved in isopropyl alcohol (100 mL) and heated to reflux. After 8 h, the 10 reaction was allowed to cool to ambient temperature and concentrated. Triethylamine (5.61 mL, 40.3 mmol) was added to a solution of the crude amine and di-tert-butyl dicarbonate (8.78 g, 40.3 mmol) in dichloromethane (100 mL). After 18 h, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (5% ethyl acetate/ 15 hexanes -+ 20% ethyl acetate/ hexanes) gave the title compound (5.48 g). Step B. Methyl N-[(benzyloxy)carbonyll-O- {(1S)-2-[(tert butoxycarbonyl)(cyclopropylmethyl)aminol-1-phenyleth yI}-D-serinate Boron trifluoride diethyl etherate (0.10 mL, 0.84 mmol) was added to a solution 20 of tert-butyl cyclopropylmethyl[(2S)-2-hydroxy-2-phenylethyllcarbamate (2.45 g, 8.39 mmol) and 1-benzyl 2-methyl (2R)-aziridine-1,2-dicarboxylate (1.97 g, 8.39 mmol) in chloroform (20 mL). After 3 h, the reaction was concentrated. Purification by silica gel chromatography (100% hexanes -> 30% ethyl acetate/ hexanes) gave the title compound (1.21 g). - 91 - WO 2004/092166 PCT/US2004/010851 Step C. N-[(Benzyloxy)carbonyll-0-(1S)-2-[(tert-butoxycarbonyl) (cyclopropylmethyl)amino] I -phenylethyl I -D-serine Aqueous sodium hydroxide (iN; 3.81 mL, 3.81 mmol) was added to a solution of methyl N-[(benzyloxy)carbonyl]-0-{(1S)-2-[(tert-butoxycarbonyl)(cyclopropylmethyl)amino]-1 5 phenylethyl}-D-serinate (1.30 g, 2.46 mmol) in tetrahydrofuran (20 mL). After 18 h, aqueous hydrochloric acid (IN; 3.81 mL, 3.81 mmol) was added. The mixture was extracted with dichloromethane (3x), and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated to give the title compound. (1.27 g) MS 535 (M+Na). 10 Step D. Benzyl (2S,6R)-4-(cyclopropylmethyl)-5-oxo-2-phenyl-1,4-oxazepan-6-ylcarbamate Trifluoroacetic acid (5.0 mL) was added to a solution N-[(benzyloxy)carbonyl]-0 (1S)-2-[(tert-butoxycarbonyl) (cyclopropylmethyl)amino]-1-phenylethyl I-D-serine (1.27 g, 2.47 mmol) in dichloromethane (15 mL). After 2 h, the mixture was concentrated and azeotroped with toluene (3x) to give the crude amine. Diphenylphosphoryl azide (1.07 ml, 4.95 mmol) was 15 added to a solution of the crude amine and 4-methylmorpholine (0.82 mL, 7.41 mmol) in NN dimethylformamide (100 mL). After 18 h, the mixture was concentrated and water was added. The mixture was extracted with ethyl acetate, and the organic layer was washed with water (2x) and saturated brine, dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography (5% ethyl acetate/ hexanes -> 50% ethyl acetate/ hexanes) gave the 20 title compound (0.426 g). MS 395 (M+1). Step E. (2S,6R)-6-Amino-4-(cyclopropylmethyl)-2-phenyl-1,4-oxazepan-5-one 10% Palladium on carbon (20 mg) was added to a solution (2S,6R)-6-amino-4 (cyclopropylmethyl)-2-phenyl-1,4-oxazepan-5-one (179 mg, 0.454 mmol) in ethanol (15 mL). 25 The reaction vessel was evacuated and back-filled with nitrogen (3x), then back-filled with hydrogen (1 atm). After 18 h, the mixture was filtered and concentrated to give the title compound (113 mg). MS 261 (M+1). 'H NMR (500 MHz, CDCl 3 ) 8 7.40-7.31 (m, 5H), 4.53 (d, J = 8.5 Hz, 1H), 4.10-4.03 (m, 2H), 3.90 (dd, J = 15.9, 7.1 Hz, IH), 3.80-3.65 (m, 2H), 3.36 (d, J = 15.9 Hz, 1H), 3.03 (dd, J = 13.9, 6.6 Hz, 1H), 1.06-1.01 (m, 1H), 0.64-0.53 (m, 2H), 0.33-0.25 30 (in, 2H). - 92 - WO 2004/092166 PCT/US2004/010851 INTERMEDIATE 65 CF3 N

-""NH

2 F F (2S,6R)-6-Amino-2-(2,3-difluorophenyl)-4-(2,2,2-trifluoroethyl)-1,4-oxazepan-5-one 5 The title compound was prepared using a similar procedure to Intermediate 64. MS 325 (M+l). INTERMEDIATE 66 MeO O N 3 Y 106 tert-Butyl r 1-(2-methoxyethyl)-2-oxo-6-phenylazepan-3-yllacetate Step A. 1-(2-Methoxyethyl)-6-phenylazepan-2-one Sodium hydride (60% dispersion in mineral oil; 0.32 g, 8.03 mmol) was added to 15 a solution of 6-phenylazepan-2-one (0.76 g, 4.02 mmol) in NN-dimethylformamide (15 mL) at 0 0 C, followed by the addition of 2-bromoethyl methyl ether (0.837 g, 6.03 mmol), and the mixture was allowed to warm to ambient temperature. After 21 h, water was added and the mixture was extracted with ethyl acetate (3x). The combined organic extracts were washed with water (3x), saturated brine, dried over sodium sulfate, filtered and concentrated. MS 248 (M+1). 20 Step B. tert-Butyl 1 -(2-methoxyethyl)-2-oxo-6-phenylazepan-3-yll acetate Lithium diisopropylamide (1.8 M in heptane/tetrahydrofuran/ethylbenzene; 0.58 g, 5.41 mmol) was added to a solution of 1-(2-methoxyethyl)-6-phenylazepan-2-one (1.03 g, 4.16 - 93 - WO 2004/092166 PCT/US2004/010851 mmol) in tetrahydrofuran (40 mL) at -78 'C. After 2 h, tert-butylbromoacetate was added. After an additional 1.5 h, the reaction was quenched with methanol and allowed to warm to ambient temperature and concentrated. Purification by reverse phase HPLC (C-18, 95% water/ acetonitrile -+ 5% water/ acetonitrile with 0.1% trifluoroacetic acid) gave 450 mg (cis isomer) 5 and 350 mg (trans isomer) of the title compound. MS 362 (M+1). cis isomer: 1H NMR (500 MHz, CDCl3) 8 7.29 (t, J = 7.6 Hz, 2H), 7.26 (m, 1H), 7.22-7.20 (m, 2H), 4.04 (br d, J = 15.2 Hz, 1H), 3.84 (dt, J = 13.9, 4.9 Hz, 1H), 3.51 (dd, J = 15.4, 3.9 Hz, 1H), 3.40-3.35 (m, 1H), 3.30 3.21 (m, 2H), 3.24 (s, 3H), 3.02-3.00 (m, 1H), 2.84 (dd, J = 16.4, 7.6 Hz, 1H), 2.68-2.66 (m, 1H), 2.33 (dd, J= 16.4, 6.8 Hz, 1H), 2.11-2.07 (m, IH), 2.05-1.95 (m, 1H), 1.80-1.76 (m, 2H), 1.46 (s, 10 9H). trans isomer: lH NMR (500 MHz, CDCl3) 6 7.32 (t, J = 7.3 Hz, 2H), 7.24-7.21 (m, 1H), 7.18 (d, J = 7.1 Hz, 2H), 3.96 (dd, J = 14.9, 10.0 Hz, 1H), 3.82-3.77 (m, 1H), 3.56-3.46 (m, 2H), 3.43-3.38 (m, 1H), 3.34 (s, 3H), 3.30 (d, J = 15.1 Hz, 1H), 3.20-3.15 (m, IH), 2.85 (dd, J = 16.6, 7.8 Hz, 1H), 2.78 (br t, 1H), 2.26 (dd, J= 16.6, 6.6 Hz, 1H), 2.10 (br d, J = 22.7, 9.3 Hz, 1H), 1.77-1.73 (m, 1H), 1.62-1.59 (m, 1H), 1.46 (s, 9H). 15 INTERMEDIATE 67 L O N 3% 0 20 tert-Butyl [1 -(cyclopropylmethy)-2-oxo-6-phenylazepan-3-yllacetate The title compounds (both cis and trans) were prepared with cyclopropylmethyl bromide and 6-phenylazepan-2-one using a similar procedure to Intermediate 66. MS 358 (M+1). 25 - 94 - WO 2004/092166 PCT/US2004/010851 INTERMEDIATE 68 H O F N F

"'NH

2 (3R,6S)-3-Amino-6-(2,3-difluorophenyl)azepan-2-one Step A. 2-Bromo-N-(2,4-dimethoxvbenzyl)prop-2-en- 1-amine 5 Triethylamine (16.0 mL, 114 mmol) was added to a solution of 2,4 dimethoxybenzylamine hydrochloride (11.1 g, 54.5 mmol) and 2,3-dibromopropene (10.9 g, 54.5 mmol) in dichloromethane (200 mL). After 18 h, water was added and the mixture was extracted with dichloromethane (3x). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel 10 chromatography [100% dichloromethane -+ 95% dichloromethane/ 5% (10% ammonium hydroxide/ methanol)] gave the title compound (7.85 g). Step B. Benzyl (1R)-1-{ [(2-bromoprop-2-enyl)(2,4-dimethoxybenzyl) aminolcarbonyl I but-3 enylcarbamate 15 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (55 mg, 0.285 mmol) was added to a solution of 2-bromo-N-(2,4-dimethoxybenzyl)prop-2-en-1-amine (73 mg, 0.256 mmol) and (2R)-2-{[(benzyloxy)carbonyl]aminoIpent-4-enoic acid (71 mg, 0.285 mmol) in dichloromethane (5 mL). After 18 h the mixture was concentrated. Purification by silica gel chromatography (5% ethyl acetate/ hexanes - 30% ethyl acetate/ hexanes) gave the title 20 compound (77 mg). MS 517 (M+1). Step C. Benzyl (R)-1-{ [[2-(2,3-difluorophenyl)prop-2-enyll(2,4 dimethoxybenzyl)aminolcarbonyl Ibut-3-enylcarbamate Dichloro[ 1,1 '-bis(diphenylphosphino)ferrocene]palladi um dichloromethane 25 adduct (0.726 g, 0.889 mmol) was added to a solution of benzyl (IR)-1-{ [(2-bromoprop-2 enyl)(2,4-dimethoxybenzyl) amino]carbonyl}but-3-enylcarbamate (9.2 g, 17.8 mmol), 2,3 difluorophenylboronic acid (2.95 g, 18.7 mmol) and sodium carbonate (2M in water; 19.6 mL, 39.1 mmol) in NN-dimethylformamide (60 mL) and the mixture was heated to 75 'C. After 2 h, the mixture was allowed to cool to ambient temperature and extracted with dichloromethane 30 (3x). The combined organic extracts were washed with saturated brine, dried over magnesium - 95 - WO 2004/092166 PCT/US2004/010851 sulfate, filtered and concentrated. Purification by silica gel chromatography (5% ethyl acetate/ hexanes -> 55% ethyl acetate/ hexanes) gave the title compound (6.8 g). MS 551.2 (M+1). Step D. Benzyl (3R)-6-(2,3-difluorophenyl)-I-(2,4-dimethoxybenzyl)-2-oxo-2,3,4,7-tetrahydro 5 1H-azepin-3-ylcarbamate [1,3-bis-(2,4,6-Trimethylphenyl-2 imidazolidinylidene)dichloro(phenylmethylene)-(tricyclohexylphosphine)ruthenium] (Grubbs second generation catalyst) (2.62 g, 3.09 mmol) was added to a solution of benzyl (IR)-1-{[[2 (2,3-difluorophenyl)prop-2-enyl](2,4-dimethoxybenzyl)amino]carbonyl}but-3-enylcarbamate 10 (6.8 g, 12.35 mmol) in dichloromethane (1800 mL) and the solution was heated to 40'C. After 48 h, additional catalyst was added (0.52 g, 0.61 mmol) and the reaction continued to heat at 40 'C for an additional 48 h. The mixture was allowed to cool to ambient temperature and concentrated. Purification by silica gel chromatography (5% ethyl acetate/ hexanes -> 55% ethyl acetate/ hexanes) gave the title compound (3.71 g). MS 523.1 (M+1). 15 Step E. Benzyl (3R)-6-(2,3-difluorophenyl)-2-oxo-2,3,4,7-tetrahydro-IH-azepin-3-ylcarbamate Trifluoroacetic acid (60 mL) was added to a solution of benzyl (3R)-6-(2,3 difluorophenyl)-1-(2,4-dimethoxybenzyl)-2-oxo-2,3,4,7-tetrahydro-IH-azepin-3-ylcarbamate (3.70 g, 7.08 mmol) in dichloromethane (40 mL). After 18 h, the mixture was concentrated at 25 20 'C, methanol (150 mL) was added, and the precipitate filtered. The filtrate was concentrated, diluted with dichloromethane (100 mL), washed with water (2x), saturated aqueous sodium bicarbonate (2x), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (5% ethyl acetate/ hexanes -+ 65% ethyl acetate/ hexanes) gave the title compound (1.75 g). MS 373.1 (M+l). 25 Step F. tert-Butyl (3R,6S)-6-(2,3-difluorophenyl)-2-oxoazepan-3-ylcarbamate 10% Palladium on carbon (700 mg) was added to a solution of benzyl (3R)-6 (2,3-difluorophenyl)-2-oxo-2,3,4,7-tetrahydro-1H-azepin-3-ylcarbamate (2.6 g, 6.98 mmol) and di-tert-butyl dicarbonate (5.03 g, 23.0 mmol) in toluene (200 mL). The reaction vessel was 30 evacuated and back-filled with nitrogen (3x), then back-filled with hydrogen (1 atm). After 24 h, the mixture was filtered and concentrated. Purification by preparative reverse phase chromatography (DeltaPak C18, 15 pt, 47 mm x 300 mm, 70 mL/min : 80% H 2 0/NH 4 OAc : 20%

CH

3 CN to 100% CH 3 CN over 60 min) afforded the pure trans title compound (1.2 g). MS 341.2 (M+1). IH NMR (500 MHz, CDCl3) 8 7.07-7.04 (m, 2H), 6.91-6.89 (m,IH), 6.04 (br s, 1H), - 96 - WO 2004/092166 PCT/US2004/010851 5.93 (d, J= 5.6 Hz, 1H), 4.46 (dd, J= 10.5, 4.6 Hz, 1H), 3.65-3.59 (m, 1H), 3.21 (dd, J= 15.1, 7.3 Hz, 1H), 3.05-3.00 (m, 1H), 2.25-2.20 (m, I H), 2.17-2.10 (m, 2H), 1.79-1.71 (m, I H), 1.46 (s, 9H). 5 Step G. (3R,6S)-3-Amino-6-(2,3-difluorophenyl)azepan-2-one Trifluoroacetic acid (4 mL) was added to a solution of tert-butyl (3R,6S)-6-(2,3 difluorophenyl)-2-oxoazepan-3-ylcarbamate (82 mg, 0.241 mmol) in dichloromethane (4 mL). After 1 h, the solution was concentrated. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with dichloromethane (3x). The combined organic extracts 10 were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. MS 241.0 (M+1) Alternatively, Intermediate 68 can be made in the following manner: Step H. 1-Benzyl 5-methyl N,N-bis(tert-butoxycarbonyl)-D-glutamate 15 To a solution of Boc-D-Glu-OBn (50.0 g, 148.2 mmol) in DCM (400 ml) and MeOH (100 ml) was added trimethylsilyldiazomethane (88.9 mL of 2.0 M solution in hexanes, 117.8 mmol) at 0 'C dropwise via an addition funnel. After 60 min the reaction was concentrated. This residue was diluted with CH 3 CN (400 mL) and (Boc) 2 0 (48.5 g, 222.3 mmol) was added followed by DMAP (18.1 g, 14.8 mmol). After 24 h the reaction was 20 concentrated and purified by silica gel chromatography (10% -> 60% ethyl acetate/ hexanes) to give the title compound (48.20 g, 72%). MS 252.2 (M+1 - 2Boc). Step I. Benzyl (2R,5E)-2-[bis(tert-butoxycarbonyl)aminol-6-nitrohex-5-enoate To a -78 'C of 1-benzyl 5-methyl N,N-bis(tert-butoxycarbonyl)-D-glutamate (48.2 25 g, 106.8 mmol) in Et 2 0 (400 mL), was added DIBAL (133.4 mL of 1.0 M solution in toluene, 133.4 mmol) slowly so as not to let the internal temperature exceed -65 'C. After 15 min, 20 mL more of DIBAL was added. After stirring for additional 20 min, water (300 mL) was added and the reaction was warmed to room temperature and stirred for 30 min. This mixture was further diluted with Et 2 O and H 2 0, the layers separated and the aqueous phase extracted with more Et 2 0. 30 The combined organics extracts were washed with a saturated aqueous solution of sodium potassium tartrate (2x), brine, dried over magnesium sulfate, filtered and concentrated to give benzyl N, N-bis(tert-butoxycarbonyl)-5-oxo-D-norvalinate (44.4 g) which was carried directly into the next step. MS 444.1 (M+Na). This material was dissolved in toluene (310 mL) and nitromethane (57.1 mL, 1.05 mol) and 1,1,3,3-tetramethylguanidine (1.3 mL, 10.5 mmol) were - 97 - WO 2004/092166 PCT/US2004/010851 added at 0 'C. After stirring for 30 min the nitroaldol reaction was complete, so methanesulfonyl chloride (12.2 mL, 158 mmol) was added followed triethylamine (22.0 mL, 158 mmol) at 0 'C and the reaction was allowed to warm to RT. After I h, 4 mL MsCl and 5.5 mL triethylamine were added. After stirring for an additional 30 min the mixture was diluted with Et 2 O and 5 NaHCO 3 , the phases separated and the aqueous layer backwashed with another portion of Et 2 0. The combined organics were dried over magnesium sulfate, filtered and concentrated to give a residue that was purified by silica gel chromatography (5% -> 50% ethyl acetate/ hexanes) to give the title compound (34.3 g, 70%). MS 487.1 (M+Na). 10 Step J. Benzyl (5S)-NN-bis(tert-butoxycarbonyl)-5-(2,3-difluorophenyl)-6-nitro-D-norleucinate A solution of benzyl (2R,5E)-2-[bis(tert-butoxycarbonyl)amino]-6-nitrohex-5 enoate (34.0 g, 73.2 mmol), 2,3-difluorophenylboronic acid (28.9 g, 183.0 mmol) and water (4.62 mL, 256.2 mmol) in dioxane (240 mL) was degassed with argon for 15 min. To this solution was added sodium bicarbonate (3.08 g, 36.6 mmol), (S)-BINAP (1.28 g, 2.05 mmol) and 15 acetylacetanotobis(ethylene)rhodium(I) (0.472 g, 1.83 mmol) . The mixture was stirred at RT for 2 min then heated to 35 'C. After 4 h, 255 mg of (S)-BINAP and 94 mg of acetylacetanotobis(ethylene)rhodium(I) were added. After an additional 2 h the reaction was diluted with DCM/NaHCO 3 , the layers separated and the aqueous phase was backwashed with another portion of DCM. The combined organics were dried over magnesium sulfate, filtered 20 and concentrated to give a residue that was purified by silica gel chromatography (5% -> 60% ethyl acetate/ hexanes) to give the title compound (37.0 g, 87%) contaminated with -5% 5R isomer. MS 379.1 (M+1 - 2Boc). Step K. (5S)-N2,N2-Bis(tert-butoxycarbonyl)-5-(2,3-difluorophenyl)-D-lysine 25 A solution of benzyl (5S)-NN-bis(tert-butoxycarbonyl)-5-(2,3-difluorophenyl)-6 nitro-D-norleucinate (15.5 g, 26.8 mmol) and 10% Pd/C (12.0 g) in EtOH (175 mL, SureSeal from Aldrich), was hydrogenated at 55 psi overnight. After 18 h, another 4 g of 10% Pd/C was added and the reaction hydrogenated at 55 psi for another 18 h. The reaction was filtered through Celite with more EtOH and concentrated to afford the title compound (12.0 g). MS 459.2 (M+ 1). 30 Step L. tert-Butyl (3R,6S)-6-(2,3-di fl uorophenyl)-2-oxoazepan-3 -ylcarbamate To a solution (5S)-N2,N2-bis(tert-butoxycarbonyl)-5-(2,3-difluorophenyl)-D-lysine (22.0 g, 48.0 mmol) in DCM (700 mL) were added EDC (11.0 g, 57.6 mmol) and HOAT (3.27 g, 24.0 mmol) followed by triethylamine (10.0 mL, 72.0 mmol). After 60 min, NaHC0 3 was added, - 98 - WO 2004/092166 PCT/US2004/010851 the layers separated and the aqueous phase backwashed with DCM. The combined organics were dried over magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (10% MeOH / DCM) to give the cyclized compound (18.0 g). A portion of this material (2.60 g, 5.90 mmol) was diluted DCM (60 mL) and TFA (1.20 mL, 11.8 mmol) was 5 added. After 1 h, NaHCO 3 was added, the layers separated and the aqueous phase backwashed with DCM. The combined organics were dried over magnesium sulfate, filtered and concentrated and the residue purified by silica gel chromatography (5% -+ 50% EtOAc / DCM) to give the title compound (1.14 g). MS 341.1 (M+1). 10 INTERMEDIATE 69 S/ S ?0 N F F

"'NH

2 (3R,6S)-3-Amino-6-(2,3-difluorophenyll-1-[2-(methylthio)ethyllazepan-2-one Step A. tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-1-[2-(methylthio)ethyll-2-oxoazepan-3 15 ylcarbamate Sodium hydride (60% dispersion in mineral oil; 40 mg, 0.600 mmol) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-oxoazepan-3-ylcarbamate (170 mg, 0.500 mmol) in N,N-dimethylformamide (4 mL) at 0 *C. After 5 min the mixture was cooled to -30 'C and 1-iodo-2-(methylthio)ethane [prepared according to known procedures: J. Org. 20 Chem., 1987, 52, 2299-2301 (158 mg, 0.782 mmol)] was added. Additional sodium hydride (33 mg, 0.50 mmol) was added and after 4 h excess sodium hydride (33 mg, 0.50 mmol) and 1-iodo 2-(methylthio)ethane (75.6 mg, 0.374 mmol) were added. After 3 h, the final portions of sodium hydride (33 mg, 0.50 mmol) and 1-iodo-2-(methylthio)ethane (75.6 mg, 0.374 mmol) were added and the mixture stirred at -20 'C overnight. The reaction was quenched with water and the 25 mixture was extracted with ethyl acetate. The organic layer was washed with water (3x), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica - 99 - WO 2004/092166 PCT/US2004/010851 gel chromatography (0% ethyl acetate/ hexanes -4 50% ethyl acetate/ hexanes) gave the title compound (77 mg). MS 415 (M+1). Step B. (3R,6S)-3-Amino-6-(2,3-difluorophenyl)-1-[2-(methylthio)ethyllazepan-2-one 5 Trifluoroacetic acid (2 mL) was added to a solution of tert-butyl (3R,6S)-6-(2,3 difluorophenyl)-1-[2-(methylthio)ethyl]-2-oxoazepan-3-ylcarbamate (77 mg, 0.186 mmol) in dichloromethane (10 mL). After 30 min, the solution was concentrated and azeotroped with toluene (2x). Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with dichloromethane (3x). The combined organic extracts were washed with saturated 10 brine, dried over magnesium sulfate, filtered and concentrated. MS 315.2 (M+1). INTERMEDIATE 70 0 N F F

""NH

2 (3R,6S)-3-Amino-6-(2,3-difluorophenyl)-1-f2-(methylsulfinyl)ethyllazepan-2-one 15 Step A. tert-Butyl (3R,6S)-6-(2,3-difluorophenyl)-I-[2-(methylsulfinyl)ethyll-2-oxoazepan-3 ylcarbamate Sodium periodate (11.3 mg, 0.053 mmol) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-1-[2-(methylthio)ethyl]-2-oxoazepan-3-ylcarbamate (22 mg, 0.053 mmol) in methanol (2 mL) and water (2 mL). After 30 min excess sodium periodate (22 20 mg, 0.11 mmol) was added. After 18 h, saturated aqueous sodium carbonate was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium carbonate (3x), saturated brine, dried over magnesium sulfate, filtered and concentrated to give the title compound. MS 431 (M+1). 25 Step B. (3R,6S)-3-Amino-6-(2,3-difluorophenyl)-1-[2-(methylsulfinyl)ethyllazepan-2-one Trifluoroacetic acid (1 mL) was added to a solution of tert-butyl (3R,6S)-6-(2,3 difluorophenyl)-I-[2-(methylsulfinyl)ethyl]-2-oxoazepan-3-ylcarbamate (23 mg, 0.053 mmol) in - 100 - WO 2004/092166 PCT/US2004/010851 dichloromethane (2 mL). After 3 h, the solution was concentrated. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with dichloromethane (3x). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated to give the title compound. MS 331 (M+1). 5 INTERMEDIATE 71 Ozes/ 0 N F F& "NH2 (3R,6S)-3-Amino-6-(2,3-difluorophenyl)-I-[2-(methylsulfonyl)ethyllazepan-2-one Step A. tert-Butyl (3R,6S)-6-(2,3-difluorophenyl)-1-r2-(methylsulfonyl)ethyll-2-oxoazepan-3 10 ylcarbamate Oxone @ (16.1 mg, 0.11 mmol) was added to a solution of tert-butyl (3R,6S)-6 (2,3-difluorophenyl)-1-{2-(methylthio)ethyl]-2-oxoazepan-3-ylcarbamate (22 mg, 0.053 mmol) in methanol (2 mL) and water (2 mL) . After 6 h excess oxone (32 mg, 0.22 mmol) was added. After 18 h, the reaction was quenched with aqueous sodium sulfite solution and the mixture was 15 extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium carbonate (3x), saturated brine, dried over magnesium sulfate, filtered and concentrated to give the title compound. MS 447 (M+1). Step B. (3R,6S)-3-Amino-6-(2,3-difluorophenyl)-1-[2-(methylsulfonyl)ethyllazepan-2-one 20 Trifluoroacetic acid (1 mL) was added to a solution of tert-butyl (3R,6S)-6-(2,3 difluorophenyl)-I-[2-(methylsulfonyl)ethyl]-2-oxoazepan-3-ylcarbamate (23.7 mg, 0.053 mmol) in dichloromethane (2 mL). After 4 h, the solution was concentrated. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with dichloromethane (3x). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, 25 filtered and concentrated to give the title compound. MS 347 (M+I). - 101 - WO 2004/092166 PCT/US2004/010851 INTERMEDIATE 72 / ?0 F N F "'NH 2 (3R,6S)-3-Amino-6-(2,3-difluorophenyl)- 1-(2-methoxyethyl)azepan-2-one Step A. tert-Butyl (3R,6S)-6-(2,3-difluorophenyl)-1-(2-methoxyethyl)-2-oxoazepan-3 5 ylcarbamate Sodium hydride (60% dispersion in mineral oil; 17.6 mg, 0.264 mmol) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-oxoazepan-3-ylcarbamate (75 mg, 0.220 mmol) in N,N-dimethyl formamide (2 mL) at 0 *C . After 5 min, 2-bromoethyl methyl ether (0.025 mL, 0.264 mmol) was added and the mixture was allowed to warm to ambient 10 temperature. After 3 h, the reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was washed with water (2x), saturated brine, dried over magnesium sulfate, filtered and concentrated to give the title compound. MS 421 (M+Na). Step B. (3R,6S)-3-Amino-6-(2,3-difluorophenyl)-I-(2-methoxyethyl)azepan-2-one 15 Trifluoroacetic acid (2.5 mL) was added to a solution of tert-butyl (3R,6S)-6 (2,3-difluorophenyl)-1-(2-methoxyethyl)-2-oxoazepan-3-ylcarbamate (99 mg, 0.248 mmol) in dichloromethane (5 mL). After 1 h, the solution was concentrated and azeotroped with toluene (2x). Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with dichloromethane (3x). The combined organic extracts were washed with saturated brine, 20 dried over magnesium sulfate, filtered and concentrated. MS 299.2 (M+1). 25 - 102 - WO 2004/092166 PCT/US2004/010851 INTERMEDIATE 73 F F F O F N F ""NH 2 (3R,6S)-3-Amino-6-(2,3-difluoropheny)-1-(2,2,2-trifluoroethyl)azepan-2-one Step A: tert-Butyl (3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3 5 ylcarbamate Sodium hydride (60% dispersion in mineral oil; 70.7 mg, 1.06 mmol) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-oxoazepan-3-ylcarbamate (301 mg, 0.884 mmol) in NN-dimethylformamide (7 mL) at -35 'C. After 15 min, 2,2,2-trifluoroethyl trichloromethanesulfonate (0.314 mL, 1.91 mmol) was added and the reaction was stirred at -35 10 'C. After 30 min, an additional amount of sodium hydride (27 mg, 0.40 mmol) and 2,2,2 trifluoroethyl trichloromethanesulfonate (0.140 mL, 0.85 mmol) were added. After 2 h, the reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was washed with water (3x), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (0% ethyl acetate/ hexanes -- + 30% ethyl 15 acetate/ hexanes) gave the title compound (306 mg). MS 423 (M+1). Step B: (3R,6S)-3-Amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one Trifluoroacetic acid (2.5 mL) was added to a solution of tert-butyl (3R,6S)-6 (2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-ylcarbamate (135 mg, 0.320 mmol) 20 in dichloromethane (5 mL). After 30 min, the solution was concentrated and azeotroped with toluene (2x). Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with dichloromethane (3x). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. MS 323.1 (M+1). 'H NMR (500 MHz, CDCl 3 ) 8 7.11-7.03 (m, 2H), 6.93-6.89 (m, 1H), 4.21-4.13 (m, IH), 4.10-3.98 (m, 2H), 25 3.85 (d, J= 11.0 Hz, 1H), 3.35 (d, J= 15.4 Hz, 1H), 3.04-2.99 (m, 1H), 2.13-2.09 (m, 2H), 2.08 2.02 (m, 1H), 1.78-1.70 (m, 3H). - 103 - WO 2004/092166 PCT/US2004/010851 INTERMEDIATE 74 0 N F N F

""NH

2

I

(3R,6S)-3-Amino-6-(2,3-difluorophenyl)-1-(pyridin-2-ylmethyl)azepan-2-one Step A. tert-Butyl (3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(pyridin-2-ylmethyl)azepan-3 5 ylcarbamate Sodium hydride (60% dispersion in mineral oil; 30 mg, 1.175 mmol) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-oxoazepan-3-ylcarbamate (160 mg, 0.470 mmol) in N,N-dimethylformamide (6 mL) at 0 *C. After 30 min, 2-bromomethyl pyridine (0.125 mg, 0.494 mmol) was added. After 1 h, the reaction was quenched with water and the 10 mixture was extracted with ethyl acetate. The organic layer was washed with water (2x), saturated brine, dried over magnesium sulfate, filtered and concentrated to give the title compound (202 mg). MS 432.2 (M+1). Step B. (3R,6S)-3-Amino-6-(2,3-difluorophenyl)-1-(pyidin-2-ylmethyl)azepan-2-on 15 Trifluoroacetic acid (3 mL) was added to a solution of tert-butyl (3R,6S)-6-(2,3 difluorophenyl)-2-oxo-1-(pyridin-2-ylmethyl)azepan-3-ylcarbamate (202 mg, 0.468 mmol) in dichloromethane (4 mL). After 18 h, the solution was concentrated. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with dichloromethane (3x). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, 20 filtered and concentrated. MS 332.2 (M+1). 25 -104- WO 2004/092166 PCT/US2004/010851 INTERMEDIATE 75 0 N F N F

"'NH

2 (3R,6S)-3-Amino-6-(2,3-difluorophenyl)-1-pyridin-4-ylazepan-2-one Step A. tert-Butyl (3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-pyridin-4-ylazepan-3-ylcarbamate 5 4-Bromopyridine (286 mg, 1.47 mmol) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-2-oxoazepan-3-ylcarbamate (200 mg, 0.588 mmol), 4,5 bis(diphenylphosphino)-9,9-dimethylxanthene (20 mg, 0.035 mmol), tris(dibenzylideneacetone)dipalladium(O) (22 mg, 0.024 mmol), and cesium carbonate (268 mg, 0.823 mmol) in dioxane (6 mL) and the mixture was heated at 150 'C in a Personal Chemistry 10 Smith CreatorrM microwave reactor. After 30 min, an additional amount of 4,5 bis(diphenylphosphino)-9,9-dimethylxanthene (20 mg, 0.035 mmol) and tris(dibenzylideneacetone)dipalladium(0) (22 mg, 0.024 mmol) were added. After 30 min, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with water (2x), saturated brine, dried over magnesium sulfate, filtered and concentrated to give the 15 title compound (55 mg). MS 418.2 (M+1). Step B. (3R,6S)-3-Amino-6-(2,3-difluorophenyl)-1-pyridin-4-ylazepan-2-one Trifluoroacetic acid (2 mL) was added to a solution of tert-butyl (3R,6S)-6-(2,3 difluorophenyl)-2-oxo-1-pyridin-4-ylazepan-3-ylcarbamate (55 mg, 0.132 mmol) in 20 dichloromethane (2 mL). After 1 h, the solution was concentrated. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with dichloromethane (3x). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. MS 318.2 (M+1). 25 Essentially following the procedures outlined for the preparation of Intermediates 69-75, the Intermediates in Table 1-4 were prepared. - 105 - WO 2004/092166 PCT/US2004/010851 TABLE 1-4 R 0 o F N F

".NH

2 Intermediate R MS (M+1) 76

CH

3 255.2 77

CH

2

CH

3 269.2 78

OCH

2 295.2 79

CH

2

CH

2 F 287 80

CH

2

CHF

2 305.1 81

H

2 C-0 325.2 82 325.2 83

CH

2

CO

2

CH

3 313.1 84 317.2 85 N 318.1 86 SO2CH3 395.1 - 106

-

WO 2004/092166 PCT/US2004/010851 87 395.1 30 2

CH

3 88 H2-q/362.2 89 HC Q /332 90 H 2 C- C N 332 91 -0\- 327 92 \0\C2313 9 \I2'- \-CH 2 325 94 F3C-\ CH2 5 95 H2 -348 ND 96 ON--C2338 -107 - WO 2004/092166 PCT/US2004/010851 97 0 354 NGCH _ 98 312

CH

2

CO

2

CH(CH

3

)

2 99 341 100 H 418.2 Cbz -N -CH 2 101 352 _________NUCH, 102 Cbz 432 /N -CH2 103 N 367 N CH 104 CH 2

CH

2 CF3 337 105 341 Me0 2 c CH, 106 N 333 N CH 2 - 108 - WO 2004/092166 PCT/US2004/010851 5 INTERMEDIATE 107 HO 0 N -"'INH2 F F (3R,6S)-3-Amino-6-(2,3-difluorophenyl)-1-(2-hydroxy-2-methylpropyl)azepan-2-one 10 Step A. Di-tert-butyl [(3R,6S)-6-(2,3-difluoropheny)-1-(2-hydroxy-2-methylpropyl)-2 oxoazepan-3-yllimidodicarbonate A solution of (5S)-N 2,N2-bis(tert-butoxycarbonyl)-5-(2,3-difluorophenyl)-D-lysine (0.569 g, 1.24 mmol), 1-chloro-2-methyl-2-propanol (0.202 g, 1.86 mmol) and diisopropylethylamine (0.529 g, 4.10 mmol) in EtOH (5 mL) was heated at 75 'C overnight. The 15 reaction was concentrated to dryness, diluted with DCM (20 mL) and EDC (0.358 g, 1.87 mmol), HOAT (0.252 g, 1.87 mmol) were added followed by diisopropylethylamine (0.650 mL, 3.73 mmol). After stirring overnight, NaHCO 3 was added, the layers separated and the aqueous phase backwashed with DCM. The combined organics were dried over magnesium sulfate, filtered, concentrated and the residue purified by silica gel chromatography (10% -4 35% EtOAc / 20 hexanes) to give the title compound (0.21 g). MS 513.1 (M+1). 'H NMR (500 Miz, CD 3 0D) 6 7.1 (m, 3H), 5.24 (d, J= 10.7 Hz, 1H), 4.02 (m, 1H), 3.69 (d, J= 13.9 Hz, 1H), 3.60 (d, J= 15.1 Hz, 1H), 3.39 (m, IH), 3.24 (d, J= 14.2 Hz, 1H), 2.4 (m, 1H), 2.1 (m, 3H), 1.5 (s, 18H), 1.20 (s, 3H), 1.16 (s, 3H). 25 Step B. (3R,6S)-3-Amino-6-(2,3-difluorophenyl)-I-(2-hydroxy-2-methylpropyl)azepan-2-one A solution of di-tert-butyl [(3R,6S)-6-(2,3-difluorophenyl)-1-(2-hydroxy-2 methylpropyl)-2-oxoazepan-3-yl]imidodicarbonate (0.095 g, 0.185 mmol) in DCM (10 mL) was - 109 - WO 2004/092166 PCT/US2004/010851 treated with trifluoroacetic acid (3 mL). After I h the reaction was concentrated to dryness to afford the title compound as a TFA salt. MS 313.2 (M+1). INTERMEDIATE 108 5 N 0 N

.INH

2 F F (3R,6S)-3-Amino-6-(2,3-difluorophenyl)-1-(1,3-thiazol-2-ylmethyl)azepan-2-one Step A. Di-tert-butyl [(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(1,3-thiazol-2-ylmethyl)azepan-3 10 yllimidodicarbonate A solution of (5S)-N 2

,N

2 -bis(tert-butoxycarbonyl)-5-(2,3-difluorophenyl)-D-lysine (0.871 g, 1.90 mmol), 2-formylthiazole (0.183 g, 1.62 mmol) and acetic acid (0.137 g, 2.28 mmol) in 1,2-dichloroethane (20 mL) was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (0.604 g, 2.85 mmol) was added and the reaction stirred overnight. The 15 reaction was diluted with saturated aqueous sodium bicarbonate, the layers separated, and the aqueous phase extracted with DCM (2x). The organic washes were combined, dried over magnesium sulfate, and concentrated. This residue was diluted with dichloromethane (20 mL) and EDC (0.569 g, 2.97 mmol), HOAT (0.401 g, 2.97 mmol) were added followed by diisopropylethylamine (1.04 mL, 5.94 mmol). After stirring overnight, NaHCO 3 was added, the 20 layers separated and the aqueous phase backwashed with DCM. The combined organics were dried over magnesium sulfate, filtered, concentrated and the residue purified by silica gel chromatography (0% -- 40% EtOAc / hexanes) to give the title compound (0.49 g). MS 538.0 (M+1). ). 'H NMR (500 MHz, CDCl 3 ) 8 7.73 (d, J = 3.5 Hz, 1H), 7.37 (d, J = 3.4 Hz, 1H), 7.0 (m, 2H), 6.8 (m, 1H), 5.20 (d, J = 10.3 Hz, IH), 5.03 (d, J= 15.5 Hz, IH), 4.96 (d, J= 15.5 Hz, 25 1H), 3.84 (dd, J= 10.3, 15.2 Hz, 1H), 3.48 (d, J= 15.5 Hz, 1H), 2.94 (dd, J= 11.0, 11.0 Hz, 1H), 2.50 (dd, 1H), 2.0 (m, 4H), 1.5 (s, 18H). - 110 - WO 2004/092166 PCT/US2004/010851 Step B. (3R,6S)-3-Amino-6-(2,3-di fluorophenyl)-1-(1,3-thiazol-2-ylmethyl)azepan-2-one A solution of di-tert-butyl [(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(1,3-thiazol-2 ylmethyl)azepan-3-yl]imidodicarbonate (0.481 g, 0.895 mmol) in DCM (10 mL) was treated 5 with trifluoroacetic acid (3 mL). After lh the reaction was diluted with saturated aqueous sodium bicarbonate, the layers separated, and the aqueous phase extracted with DCM (2x). The organic washes were combined, dried over magnesium sulfate, and concentrated to afford the title compound (0.30 mg). MS 338.2 (M+1). 10 Essentially following the procedures outlined for the preparation of Intermediates 107-108, the Intermediates in Table I-5 were prepared. TABLE 1-5 R 0 O N F F ""NH2 15 Intermediate R MS (M+1) 109 CH(CH 3

)

2 283.2 110 CH 2

CH

2 OH 285.2 111 0 .- N 322.2

CH

2 112 N 335.2 N CH 2 N Me - 111 - WO 2004/092166 PCT/US2004/010851 113 MeN.-- N 335.2 L

>CH

2 114 Me335.2 N N/

CH

2 115 Me 352.2 116 325 Me 117 Cbz-N 444 118 311 119 OMe 313.2

CH

2 120 Ac 366

SCH

2 121 F 3 C 406 * CH 2 - 112 - WO 2004/092166 PCT/US2004/010851 122 Cbz 458 N

CH

2 123 N 350

CH

2 F 124 338

CH

2 125 OH 353.2

F

3 C

CH

2 126 O 369.1

F

3 C

CH

2 (M+H 2 0) 127 OH 299.2

CH

2 128 OMe 367.2

F

3 C

CH

2 5 10 - 113 - WO 2004/092166 PCT/US2004/010851 EXAMPLE I MeO 0 N N "NH O" N N ON N H N 5 N-f(3R,6S)-1-(2-Methoxyethyl)-2-oxo-6-phenylazepan-3-yll-4-(2-oxo-2,3-dihydro-1H imidazo[4,5-blpyndin-I-yl)piperidine- 1 -carboxamide Triethylamine (0.015 mL, 0.107 mmol) was added to a solution of (3R,6S)-3 amino-1-(2-methoxyethyl)-6-phenylazepan-2-one (28 mg, 0.107 mmol) and 4-nitrophenyl chloroformate (22 mg, 0.107 mmol) in tetrahydrofuran (2 mL) at 0 *C. After 30 min, 2-oxo-1-(4 10 piperidinyl)-2,3-dihydro-IH-imidazo[4,5-b]pyridine dihydrochloride (37 mg, 0.128 mmol), diisopropylethylamine (0.074 mL, 0.427 mmol) and dichloromethane (2.5 mL) were added and the mixture allowed to warm to ambient temperature. After 18 h, saturated aqueous sodium carbonate was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium carbonate (3x), saturated brine, dried over magnesium 15 sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane -> 93% dichloromethane/ methanol) gave the title compound (45 mg). MS 507.2737 (M+1). Essentially following the procedures outlined for the preparation of Example 1, the Examples in 20 Table E-1 were prepared. TABLE E-1 0 N 0 3 "-NH 6 C-N -N N 0 N - 114 - WO 2004/092166 PCT/US2004/010851 Examples C-3 C-6 R1 MS (M+1) 2 R S H 449 3 R R H 449 4 R S CH 3 463 5 R S CH 2

CH

3 477 6 R S CH 2

CF

3 531.2326 7 R S CH 2

CO

2

CH

3 521.2481 8 R S CH 2

CO

2 H 507.2353 9 R S (CH 2

)

2 0CH 2

CH

3 521.2910 10 R S CH 2 CN 488.2378 11 R S (CH 2

)

2 0H 493.2555 12 R S >-CH 2 503 13 R S O 535.2666 14 R S CH 2

CH

2 F 495.2489 15 R S CH 2

CHF

2 513.2401 16 R S CH 2

CHCF

2 525.2392 17 R S O -CH2 539.2747 18 R S N CH2 540.2715 - 115- WO 2004/092166 PCT/US2004/010851 19 R s H 2 O.,.- 533.2858 20 R S 47 CH9 533.2858 21 R S H 2 N CH 2 492.2712 22 R S O CH2 535.3008 23 R S O CH2 521.2856 24 R S - CH2 523.2440 25 R S 0 O 555.2379 CH, 26 R S (CH 2

)

2 0CF 3 561 27 R S O CH, 533.2850 28 R S HO CH 2 507.2703 29 R s HO 521.2867

OH

2 30 R S H 2 N CH2 506.2395 -116- WO 2004/092166 PCT/US2004/010851 31 R S HO CH 2 561.2395

F

3 C 32 R S O CH, 533.2821 33 R S Ph 525.2569 34 R S 0 534.2791 N CH 2 EXAMPLE 35 H O N O "'INH N -NNNH C ND N N HO 5 N-[(3R)-6-(4-Hydroxyphenyll-2-oxoazepan-3-yll-4-(2-oxo-2,3-dihydro-IH-imidazo[4,5 bipyridin- I -yl)piperidine- I -carboxamide Triethylamine (0.009 mL, 0.091 mmol) was added to a solution of (3R)-3-amino 10 6-(4-hydroxyphenyl)azepan-2-one (10 mg, 0.045 mmol) and 4-nitrophenyl chloroformate (18 mg, 0.091 mmol) in N,N-dimethylformamide (0.2 mL) and tetrahydrofuran (0.2 mL) at 0 'C. After I h, 2-oxo-1-(4-piperidinyl)-2,3-dihydro-IH-imidazo[4,5-blpyridine dihydrochloride (26 mg, 0.091 mmol) and diisopropylethylamine (0.032 mL, 0.182 mmol) were added and the mixture was allowed to warm to ambient temperature. After 18 h, the mixture was purified by 15 reverse phase HPLC (C-18, 95% water/ acetonitrile -> 5% water/ acetonitrile with 0.1% trifluoroacetic acid) to give the title compound (7 mg). MS 465.2243 (M+1). - 117- WO 2004/092166 PCT/US2004/010851 Essentially following the procedures outlined for the preparation of Examples 1-35, the Examples in Table E-2 were prepared. TABLE E-2 5 R 0 N 0 6 0 N Examples C-6 R1 R2 MS (M+1) 36 R or S H 467.2189 37 S H 467.2200 38 R or S H 467.2201 F 39 R or S H 467.2203 40 R or S H 485.2076 F F - 118 - WO 2004/092166 PCT/US2004/010851 41 R H 485.2090 F F 42 R or S H 450 43 R or S H 450.2241 44 R or S H N 450.2262 45 RorS > CH 2 HO 519 46 S >-CH 2 HO 519 47 S >-CH 2 /r -. 493 48 R >-CH 2 / 493

HN

49 R or S H F 485.2123 50 R or S H F F 485.2118 -119- WO 20041092166 PCT/US2004/010851 51 R or S H CFa 517.2165 52 R or S H N H3 463.2428

CH

3 53 RorS H 463.2431

CH

3 54 RorS H 463.2434 55 R or S H 483.1894 cI 56 S H 483.1907 57 R or S H 483.1907 58 R or S H 415.2457 59 R or S H 517.1516 CI CI 60 R or S H 455.2774 -120- WO 2004/092166 PCT/US2004/010851 61 R or S H 463.2480 62 R or S H 501.1808 F Cl 63 S Et F 495.2532 64 S CH 2

CH

2 F 513.2418 F 65 S CH 2

CH

2 OMe 525.2629 F 66 R or S Et 491.2777 67 R or S Me 531.2 Cl CI 68 S Me 531.2 -CI Cl_ 69 S Et 545.2 -CI -Cl - 121 - WO 2004/092166 PCT/US2004/010851 70 R or S Et 529.2123 F CI 71 R or S CH 2

CF

3 599.1538 C CI EXAMPLE 72 0 N O .'NH %-NH O. NN N NH 0 N 5 N-[(3R)-1-(Cyclopropylmethyl)-2-oxo-6-phenyl-2,3,4,7-tetrahydro-1H-azepin-3-yil-4-(2-oxo 2,3-dihydro- IH-imidazo[4,5-blpyridin- 1 -yl)piperidine- I -carboxamide The title compound was prepared using similar procedures to Examples 1-35. MS 10 501 (M+1). 15 20 - 122 - WO 2004/092166 PCT/US2004/010851 EXAMPLE 73 O N 0 '"NH N H N N 5 N-[(3R)-1-(Cyclopropylmethyl)-2-oxo-6-pyridin-4-yl-2,3,4,7-tetrahydro-1H-azepin-3-yll-4-(2 oxo-2,3-dihydro-IH-imidazor4,5-blpyridin- 1 -yl)piperidine- 1 -carbox ami de The title compound was prepared using similar procedures to Examples 1-35. MS 502 (M+1). EXAMPLE 74 10 0 N o O -"NH NN N H O N N-[(2S,6R)-4-(Cyclopropylmethyl)-5-oxo-2-phenyl- 1,4-oxazepan-6-yll-4-(2-oxo-2,3-dihydro I H-imi dazo[4,5-blpyri din-I -yl)piperidine- 1-carboxamide 15 Triethylamine (0.015 mL, 0.109 mmol) was added to a solution of (2S,6R)-6 amino-4-(cyclopropylmethyl)-2-phenyl-1,4-oxazepan-5-one (27 mg, 0.104 mmol) and 4 nitrophenyl chloroformate (22 mg, 0.109 mmol) in tetrahydrofuran (2 mL) at 0 'C. After 0.5 h, diisopropylethylamine (0.072 mL, 0.415 mmol), 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H imidazo[4,5-bJpyridine dihydrochloride (36 mg, 0.124 mmol), and dichloromethane (2.5 mL) 20 were added and the mixture warmed to ambient temperature. After 18 h, the mixture was concentrated. Purification by silca gel chromatography (100% dichloromethane -> 95% dichloromethane/ methanol) gave the title compound (45 mg). MS 505.2559 (M+1). - 123 - WO 2004/092166 PCT/US2004/010851 EXAMPLE 75 CF3 N O O "NH NN NH 0 , - N N 0 N FON 5 F N-[(2S,6R)-2-(2,3-difluorophenyl)-5-oxo-4-(2,2,2-trifluoroethyl)-1,4-oxazepan-6-yll-4-(2-oxo 2,3-dihydro- 1 H-imidazo[4,5-blpyridin- I -yl)piperidine- 1-carboxamide The title compound was prepared with using a similar procedure to Example 74. MS 569.1943 (M+1). 10 EXAMPLE 76 MeO 0 N O NN N N N H 0N 15 trans-1-(1 [1-(2-Methoxyethyl)-2-oxo-6-phenylazepan-3-yllacety I piperidin-4-yl)-2-oxo-2,3 dihydro-IH-imidazo[4,5-blpyridin-4-ium trifluoroacetate Step A. Trans-[r1-(2-methoxyethyl)-2-oxo-6-phenylazepan-3-yll acetic acid 20 Trifluoroacetic acid (1 mL) was added to a solution (trans)-tert-butyl[1-(2 methoxyethyl)-2-oxo-6-phenylazepan-3-yl] acetate (170 mg, 0.47 mmol) in dichloromethane (3 mL). After 2 h, the solution was concentrated. MS 306 (M+1). - 124 - WO 2004/092166 PCT/US2004/010851 Step B. trans-1-1 [1 -(2-Methoxyethyl)-2-oxo-6-phenylazepan-3-yllacety I piperidin-4-yi)-2 oxo-2,3-dihydro-1H-imidazo[4,5-blpyridin-4-ium trifluoroacetate Triethylamine (0.33 mL, 2.35 mmol) was added to a solution of trans-[1-(2 5 methoxyethyl)-2-oxo-6-phenylazepan-3-yl]acetic acid (143.6 mg, 0.47 mmol), 2-oxo-1-(4 piperidinyl)-2,3-dihydro-1H-imidazo[4,5-bpyridine dihydrochloride (136 mg, 0.47 mmol), 1-[3 (dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (180 mg, 0.941 mmol), and 1 hydroxybenzotriazole hydrate (72 mg, 0.47 mmol) in NN-dimethylformamide (4 mL). After 18 h, the reaction was concentrated. Purification by reverse phase HPLC (C-18, 95% 10 water/acetonitrile --> 5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (187 mg). MS 506 (M+1). - 125 - WO 2004/092166 PCT/US2004/010851 EXAMPLE 77 MeO 0 N N 0 N cis- 1-(1- [1-(2-Methoxyethyl)-2-oxo-6-phenylazepan-3-yllacety I piperidin-4-yi)-2-oxo-2,3 5 dihydro-1H-imidazof4,5-blpyridin-4-ium trifluoroacetate The title compound was prepared with (cis)-tert-butyl[1-(2-methoxyethyl)-2-oxo 6-phenylazepan-3-ylIacetate using a similar procedure to Example 76. MS 506 (M+1). Essentially following the procedures outlined for the preparation of Example 76, the Examples in 10 Table E-3 were prepared. TABLE E-3 R0 N O 6 3 N H N N O N Examples C-3 C-6 R I MS (M+1) 78 R S >-CH 2 502.2813 79 S R >-CH 2 502 80 R R >-CH 2 502 81 S S >-CH 2 502 - 126 - WO 2004/092166 PCT/US2004/010851 EXAMPLE 82 0 "'INH )WNH N O 0 N F 5 N- (3R,6S)-6-(2,3-Difluorophenyl)-I-[2-(methylthio)ethyll-2-oxoazepan-3-yI -4-(2-oxo-2,3 dihydro-IH-imidazor4,5-bipyridin-1-yl)piperidine-1-carboxamide Triethylamine (0.020 mL, 0.143 mmol) was added to a solution of (3R,6S)-3 amino-6-(2,3-difluorophenyl)- 1-[2-(methylthio)ethyllazepan-2-one (45 mg, 0.143 mmol) and 4 nitrophenyl chloroformate (29 mg, 0.143 mmol) in tetrahydrofuran (3 mL) at 0 'C. After 15 min, 10 2-oxo-1-(4-piperidinyl)-2,3-dihydro-IH-imidazo[4,5-b]pyridine dihydrochloride (46 mg, 0.157 mmol), triethylamine (0.080 mL, 0.572 mmol) and dichloromethane (5 mL) were added and the mixture was heated to 50 'C. After 30 min, the mixture was allowed to cool to ambient temperature and concentrated. Purification by silica gel chromatography [100% dichloromethane -- 95% dichloromethane/ methanol (10% ammonium hydroxide/ methanol)] gave the title 15 compound (60 mg). The title compound was converted to the HCI salt with 2M HCI in ether. MS 559.2 (M+1). 'H NMR (500 MHz, CD 3 0D) 6 8.11 (dd, J= 7.8 Hz, 1.0 Hz, 1H), 7.99 (dd, J = 6.1 Hz, 1.0 Hz, 1H), 7.38-7.35 (m, IH), 7.18-7.14 (m, 3H), 4.76 (d, J= 10.7 Hz, 1H), 4.61 4.54 (m, IH), 4.31-4.26 (m, 2H), 4.15-4.09 (m, 1H), 3.85-3.80 (m, 1H), 3.67-3.58 (m, 1H), 3.37 (d, J= 15.4 Hz, 1H), 3.20-3.16 (m, IH), 3.08-2.96 (m, 2H), 2.75-2.70 (m, 2H), 2.49-2.41 (m, 20 IH), 2.34-2.26 (m, 1H), 2.21-2.16 (m, 1H), 2.14 (s, 3H), 2.11-2.07 (m, 2H), 1.90-1.85 (m, 3H). 25 - 127 - WO 2004/092166 PCT/US2004/010851 EXAMPLE 83 0 N O 'NH N H N N FN F 5 N-I (3R,6S)-6-(2,3-Difluorophenyl)- 1-[2-(methylsulfinyl)ethyll-2-oxoazepan-3l-ylI -4-(2-oxo-2,3 dihydro- 1H-imidazof4,5-blpyridin- I -yl)piperidine- I -carboxamide Triethylamine (0.010 mL, 0.027 mmol) was added to a solution of (3R,6S)-3 amino-6-(2,3-difluorophenyl)-1-[2-(methylsulfinyl)ethyl]azepan-2-one (8.9 mg, 0.027 mmol) and 4-nitrophenyl chloroformate (5.4 mg, 0.027 mmol) in tetrahydrofuran (0.700 mL) at 0 'C. 10 After 45 min, 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine dihydrochloride (7.9 mg, 0.027 mmol) and triethylamine (0.040 mL, 0.108 mmol) were added and the mixture allowed to warm to ambient temperature. After 16 h, the mixture was concentrated. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile -- 5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound. MS 575 (M+1). 15 EXAMPLE 84 0 N 0 , .NH N0 N / : F N F - 128 - WO 2004/092166 PCT/US2004/010851 N- I (3R,6S)-6-(2,3-Difluorophenyl)-1-r2-(methylsulfonyl)ethyll-2-oxoazepan-3-yI -4-(2-oxo-2,3 dihydro-IH-i midazor4,5-blpyridin-1 -ylpiperidine-1 -carboxamide Triethylamine (0.010 mL, 0.023 mmol) was added to a solution of (3R,6S)-3 amino-6-(2,3-difluorophenyl)-1-[2-(methylsulfonyl)ethyl]azepan-2-one (8 mg, 0.023 mmol) and 5 4-nitrophenyl chloroformate (4.6 mg, 0.023 mmol) in tetrahydrofuran (0.700 mL) at 0 'C. After 15 min, 2-oxo- 1-(4-piperidinyl)-2,3-dihydro-IH-imidazo[4,5-b]pyridine dihydrochloride (6.7 mg, 0.023 mmol) and triethylamine (0.040 mL, 0.092 mmol) were added and the mixture allowed to warm to ambient temperature. After 16 h, the mixture was concentrated. Purification by reverse phase HPLC (C-18, 95% water/acetonitrile - 5% water/acetonitrile with 10 0.1% trifluoroacetic acid) gave the title compound. MS 591 (M+1). EXAMPLE 85 N / 0 N ON N NH F NN F 15 N-[(3R,6S)-6-(2,3-Difluorophenyl)-1-(2-methoxyethyl)-2-oxoazepan-3-yll-4-(2-oxo-2,3-dihydro 1H-imidazor4,5-blpyridin-1-yl)piperidine-1-carboxamide Triethylamine (0.030 mL, 0.218 mmol) was added to a solution of (3R,6S)-3 amino-6-(2,3-difluorophenyl)-1-(2-methoxyethyl)azepan-2-one (65 mg, 0.218 mmol) and 4 20 nitrophenyl chloroformate (44 mg, 0.218 mmol) in tetrahydrofuran (3 mL) at 0 'C. After 30 min, 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine dihydrochloride (70 mg, 0.240 mmol), triethylamine (0.120 mL, 0.872 mmol), and dichloromethane (5 mL) were added and the mixture allowed to warm to ambient temperature. After 4.5 h, the mixture was concentrated. Purification by silica gel chromatography [100% dichloromethane -> 95% dichloromethane/ 25 methanol (10% ammonium hydroxide/ methanol)] gave the title compound (88 mg). The title compound was converted to the HCI salt with 2M HC in ether. MS 543.3 (M+1). 'H NMR (500 MHz, CD 3 0D) 8 8.09 (dd, J = 7.8 Hz, 1.0 Hz, 1H), 7.99 (dd, J = 6.1 Hz, 1.0 Hz, 1H), - 129 - WO 2004/092166 PCT/US2004/010851 7.36(m, IH), 7.17-7.10 (m, 3H), 4.78 (d, J= 11.0 Hz, 1H), 4.61-4.54 (m, IH), 4.31-4.24 (m, 2H), 4.18-4.13 (m, 1H), 3.94-3.89 (m, IH), 3.57-3.53 (m, 2H), 3.48-3.43 (m, IH), 3.39 (d, J= 15.1 Hz, 1H), 3.34 (s, 3H), 3.19-3.15 (m, 1H), 3.07-2.96 (m, 2H), 2.49-2.41 (m, 1H), 2.35-2.26 (m, 1H), 2.19-2.06 (m, 3H), 1.90-1.76 (m, 3H). 5 EXAMPLE 86 F F F 0 NO -NH N N NH N F 10 N-[(3R,6S)-6-(2,3-Difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-vll-4-(2-oxo-2,3 di hydro- I H-imidazo[4,5-blpyridin- I -ylpiperidine-1 -carboxamide Triethylamine (0.038 mL, 0.276 mmol) was added to a solution of (3R,6S)-3 amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one (89 mg, 0.276 mmol) and 4 nitrophenyl chloroformate (56 mg, 0.276 mmol) in tetrahydrofuran (3 mL) at 0 'C. After 30 min, 15 2-oxo-1-(4-piperidinyl)-2,3-dihydro-IH-imidazo(4,5-b]pyridine dihydrochloride (88 mg, 0.304 mmol), triethylamine (0.152 mL, 1.104 mmol), and dichloromethane (5 mL) were added and the mixture allowed to warm to ambient temperature. After 48 h, the mixture was concentrated. Purification by silica gel chromatography [100% dichloromethane -+ 95% dichloromethane/ methanol (10% ammonium hydroxide/ methanol)] gave the title compound (98 mg). The title 20 compound was converted to the HCI salt with 2M HCI in ether. MS 567.2 (M+1). 'H NMR (500 MHz, CD 3 0D) 8 8.11 (dd, J = 7.8 Hz, 1.0 Hz, 1H), 8.00 (dd, J = 5.9 Hz, 1.0 Hz, 1H), 7.34 7.31 (m, IH), 7.19-7.13 (m, 3H), 4.86-4.83 (m,IH), 4.62-4.57 (m, IH), 4.49-4.41 (m, IH), 4.33 4.25 (m, 3H), 4.12-4.04 (m, 1H), 3.51-3.46 (m, 111), 3.18-3.14 (m, 1H), 3.09-2.96 (m, 2H), 2.51 2.44 (m, IH), 2.33-2.25 (m, IH), 2.22-2.10 (m, 3H), 1.90-1.81 (m, 3H). 25 - 130 - WO 2004/092166 PCT/US2004/010851 EXAMPLE 87 N\ -01 NO "NH )-NH N N N F 0N 5 F N-[(3R,6S)-6-(2,3-Difluorophenyl)-2-oxo-1-(pyridin-2-ylmethyl)azepan-3-yll-4-(2-oxo-2,3 dihydro- I H-imidazof4,5-blpyridin- 1 -yl)piperidine- I -carboxami de Triethylamine (0.065 mL, 0.468 mmol) was added to a solution of (3R,6S)-3 10 amino-6-(2,3-difluorophenyl)-1-(pyridin-2-ylmethyl)azepan-2-one (180 mg, 0.417 mmol) and 4 nitrophenyl chloroformate (94 mg, 0.468 mmol) in tetrahydrofuran (3 mL) at 0 C. After 1 h, 2 oxo- 1-(4-piperidinyl)-2,3-dihydro- 1H-imidazo[4,5-b]pyridine dihydrochloride (136 mg, 0.468 mmol) and triethylamine (0.195 mL, 1.404 mmol) were added and the mixture allowed to warm to ambient temperature. After 18 h, the mixture was partitioned between ethyl acetate and water. 15 The organic layer was washed with water (2x), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography [100% dichloromethane -> 95% dichloromethane/ methanol (10% ammonium hydroxide/ methanol)] gave the title compound (240 mg). The title compound was converted to the HCI salt with 2M HC in ether. MS 576.3 (M+1). 'H NMR (500 MHz, CD 3 0D) 8 8.78 (d, J = 5.9 Hz, IH), 8.62-8.59 (m, 1H), 20 8.07 (d, J= 8.3 Hz, 1H), 8.03-7.98 (m, 3H), 7.32 (dd, J= 8.1 Hz, 6.1, 1H), 7.18-7.15 (m, 3H), 5.43 (d, J = 16.9 Hz, 1H), 4.75 (d, J = 17.1 Hz, 1H), 4.56-4.51 (m, 1H), 4.36-4.28 (m, 3H), 3.51 (d, J = 15.1 Hz, IH), 3.48 (s, 1H), 3.22-3.17 (m, IH), 3.05-2.98 (m, 2H), 2.44-2.40 (m, 1H), 2.34-2.23 (m, 2H), 2.18-2.14 (m, 2H), 1.97-1.92 (m, 1H), 1.89-1.88 (n, 2H). - 131 - WO 2004/092166 PCT/US2004/010851 EXAMPLE 88 0 N ~N N NH "'INH N H F O N N F 5 N-[(3R,6S)-6-(2,3-Difluorophenyl)-2-oxo-1-pyridin-4-ylazepan-3-yll-4-(2-oxo-2,3-dihydro-1H imidazor4,5-blpyridin- 1-yl)piperidine-1 -carboxamide Triethylamine (0.018 mL, 0.132 mmol) was added to a solution of (3R,6S)-3 amino-6-(2,3-difluorophenyl)-1-pyridin-4-ylazepan-2-one (42 mg, 0.132 mmol) and 4 10 nitrophenyl chloroformate (27 mg, 0.132 mmol) in tetrahydrofuran (2 mL) at 0 'C. After I h, 2 oxo-1-(4-piperidinyl)-2,3-dihydro- 1H-imidazo[4,5-b]pyridine dihydrochloride (38 mg, 0.132 mmol) and triethylamine (0.054 mL, 0.396 mmol) were added and the mixture allowed to warm to ambient temperature. After 18 h, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with water (2x), saturated brine, dried over magnesium sulfate, 15 filtered and concentrated. Purification by silica gel chromatography [100% dichloromethane -+ 95% dichloromethane/ methanol (10% ammonium hydroxide/ methanol)] gave the title compound (53 mg). The title compound was converted to the HCI salt with 2M HCI in ether. MS 562.2 (M+1). 'H NMR (500 MHz, CD 3 0D) 6 8.76 (d, J= 7.6 Hz, 2H), 8.11 (d, J= 7.3 Hz, 2H), 8.00 (d, J= 6.4 Hz, 2H), 7.30 (t, J= 7.0 Hz, 1H), 7.27-7.21 (m, 3H), 5.11 (d, J= 11.5 Hz, 20 1H), 4.72-4.65 (m, 1H), 4.60-4.55 (m, 1H), 4.35-4.33 (m, 2H), 4.14 (d, J = 16.1 Hz, 1H), 3.42 3.39 (m, IH), 3.09-3.02 (m, 2H), 2.47-2.44 (m, 1H), 2.37-2.30 (m, 2H), 2.24-2.18 (m, 2H), 2.06 2.03 (m, 1H), 1.91 (br. s, 2H). 25 - 132 - WO 2004/092166 PCT/US2004/010851 EXAMPLE 89 N 0 N .mNH 0 N F 5 N-[(3R,6S)-6-(2,3-Difluorophenyl)-2-oxo-1-(1,3-thiazol-2-ylmethyl)azepan-3-yll-4-(2-oxo-2,3 dihydro- 1H-imidazo[4,5-b] pyridin-I -yl)piperidine- 1 -carboxamide Triethylamine (0.156 mL, 0.1.12 mmol) was added to a solution of (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-(1,3-thiazol 2-ylmethyl)azepan-2-one (302 mg, 0.895 mmol) and 4-nitrophenyl chloroformate (217 mg, 1.074 10 mmol) in tetrahydrofuran (15 mL) at 0 'C. After 30 min, 2-oxo-1-(4-piperidinyl)-2,3-dihydro 1H-imidazo[4,5-b]pyridine dihydrochloride (782 mg, 2.685 mmol), triethylamine (5.37 mmol) and dichloromethane (15 mL) were added and the mixture allowed to warm to ambient temperature. The reaction was stirred overnight, concentrated, diluted with saturated aqueous sodium bicarbonate and extracted with dichloromethane (2x). The organic layer was washed 15 with water, saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (0% -+ 8% methanol / dichloromethane) gave the title compound (400 mg). MS 582.2109 (M+1). 'H NMR (500 MHz, CDCl 3 ) 8 8.06 (d, J = 4.5 Hz, 1H), 7.73 (d, J = 3.4 Hz, 1H), 7.35 (m, 2H), 7.0 (m, 2H), 6.98 (dd, J 5.4, 7.8 Hz, 1H), 6.85 (m, 1H), 6.21 (d, J= 5.3 Hz, IH), 5.0 (app q, J= 15 Hz, 2H), 4.85 (dd, J= 5.0, 11.1 Hz, IH), 4.58 (m, 1H), 4.27 20 (br dd, 2H), 4.00 (dd, J= 10.6, 15.1 Hz, 1H), 3.50 (d, J= 15.1 Hz, 1H), 3.0 (br dd, 1h), 2.88 (dd, J = 10.0, 10.0 Hz, 1H), 2.2-1.6 (m, 8H). 25 - 133 - WO 2004/092166 PCT/US2004/010851 EXAMPLE 90 HO 0 NO N N NH F N F 5 N-[(3R,6S)-6-(2,3-difluorophenyl)-1-(2-hydroxy-2-methylpropyl)-2-oxoazepan-3-yfl-4-(2-oxo 2,3-dihydro-1H-imidazo[4,5-blpyridin-1-yl)piperidine-1-carboxamide Triethylamine (0.054 mL, 0.389 mmol) was added to a solution of (3R,6S)-3 amino-6-(2,3-difluorophenyl)- 1-(2-hydroxy-2-methylpropyl)azepan-2-one (54 mg, 0.173 mmol) 10 and 4-nitrophenyl chloroformate (40 mg, 0.199 mmol) in tetrahydrofuran (15 mL) at 0 'C. After 30 min, 2-oxo- 1 -(4-piperidinyl)-2,3-dihydro- 1 H-imi dazo[4,5-b]pyridine dihydrochloride (151 mg, 0.519 mmol), triethylamine (1.04 mmol) and chloroform (15 mL) were added and the mixture allowed to warm to ambient temperature. The reaction was then heated to 50*C for 2 h, concentrated, diluted with saturated afueous sodium bicarbonate and extracted with 15 dichloromethane (2x). The organic layer was washed with water, saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (1.5% -+ 11% methanol / dichloromethane) gave the title compound (70 mg). MS 557.2653 (M+1). 'H NMR (500 MHz, CDC1 3 ) 3 8.03 (d, J = 4.8 Hz, 1H), 7.34 (d, J = 7.7 Hz, 1H), 7.1 (m, 2H), 7.0 6.9 (m, 2H), 6.17 (d, J = 5.1 Hz, 1H), 4.84 (dd, J = 10.9, 5.0 Hz, 1H), 4.5 (m, 1H), 4.3 (br dd, 20 2H), 4.02 (dd, J= 10.1, 15.1 Hz, 1H), 3.76 (d, J= 14.1 Hz, 1H), 3.42 (d, J= 15.1 Hz, IH), 3.31 (d, J= 14.1 Hz, 1H), 3.15-2.95 (m, 4H), 2.3-1.9 (m, 8H), 1.26 (s, 3H), 1.24 (s, 3H). Essentially following the procedures outlined for the preparation of Examples 82-90, the Examples in Table E-4 were prepared. 25 - 134 - WO 2004/092166 PCT/US2004/010851 TABLE E-4 ONN N N F F Example R MS (M+1) 91

CH

3 499.2 92

CH

2

CH

3 513.2 93 OH 2 539.3 94 CH 2

CH

2 F 531.1 95

CH

2

CHF

2 549.1 96 H2C 0569.3 97 H, 569.3 98

CH

2

CO

2

CH

3 557.2287 99 561.2 100 562.2 - 135 - WO 2004/092166 PCT/US2004/010851 101 S02CH3 639.2 102 639.2

SO

2

CH

3 103 H606.3 N 104 O'N 566.2344

OLCH

2 105 CH(CH 3

)

2 527.2545 106 N 579.2658 N Me 107 Me N-N 579.2656

CH

2 108 Me 579.2657 -N 1 CH 2 109 s Me 596.2242 110 H2C 576.2496 - 136 - WO 2004/092166 PCT/US2004/010851 111 H2C ( N 576.2499 112 0 571 \r\-CH 2 113 CH, 557.2 114 O 569.2651 115

F

3 C.--O CH2 597.2193 116

CH

2

CO

2 H 543.2163 117 H2C 592.2433 N/ 118

CH

2

CH

2

SO

2

CH

3 591.2169 119 582.2972 120 0 598.2944 N CH 0 --,,H 2 121 556.2834 N-CH, 122 CH 2 CO2CH(CH 3

)

2 585 123 H2N. GCHq 528.3 - 137 - WO 2004/092166 PCT/US2004/010851 124 O 596.2681 125 596.3153 126 HN 554.2665 127 0 555.2526 128 CH, 542.2683 129 MeN 611.3289 N.CH 130 OMe 557.2666

CH

2 131 CH 2

CH

2

CF

3 581.2296 132 MeOp CH 585.2655 133 571

HO

2 C CH, 134 N 577.2484 __ _N CH 2 -138- WO 2004/092166 PCT/US2004/010851 135 610.2954 N,

CH

2 136 F 3 C 650.2914

CH

2 137 H 568.2834

CH

2 138 N 594.2412

CH

2 F 139 Me 582.2901 N,

SCH

2 140 CH 2

CH

2 OH 529.2383 141 OH 597.2244

F

3 C CH 2 142 O 595.2064

F

3 C CH 2 143 OH 543.2504

CH

2 144 OMe 612.3378

F

3 C CH 2 - 139- WO 2004/092166 PCT/US2004/010851 145 0 541.2362

CH

2 EXAMPLE 146 F F F O N O ,'"NH N H N N F . F N 5 N-r(3R,6S)-6-(2,3-Difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yll-4-(8-oxo-8,9 dihydro-7H-purin-7-yl)piperidine- 1 -carboxamide Triethylamine (0.030 mL, 0.215 mmol) was added to a solution of (3R,6S)-3 amino-6-(2,3-difluorophenyl)-1-(2,2,2-trifluoroethyl)azepan-2-one (80 mg, 0.248 mmol) and 4 10 nitrophenyl chloroformate (44 mg, 0.218 mmol) in tetrahydrofuran (3 mL) at 0 *C. After 0.5 h, 7 piperidin-4-yl-7,9-dihydro-8H-purin-8-one hydrochloride (73 mg, 0.248 mmol) and triethylamine (0.120 mL, 0.860 mmol) were added and the mixture allowed to warm to ambient temperature. After 18 h, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with water (2x), saturated brine, dried over magnesium sulfate, filtered and concentrated. 15 Purification by silica gel chromatography (100% dichloromethane -+ 95% dichloromethane/ methanol) gave the title compound (114 mg). MS 567.2123 (M+1). Essentially following the procedures outlined for the preparation of Example 146, the Examples in Table E-5 were prepared. 20 - 140 - WO 2004/092166 PCT/US2004/010851 TABLE E-5 R 0 O N ,N "NH N NH 0 N (;F F N Example R MS (M+1) 147 CH 3 500.2182 148 CH 2 540.2493 149 CH 2

CHF

2 550.2159 150 CH 2

CH

2 0CF 3 598.2147 151 CH 2

CH

2

SCH

3 560.2217 152 CH 2

CH

2

SOCH

3 576.2174 153 CH 2

CH

2

SO

2

CH

3 592.2 154 CH 2

CH

2 0CH 3 544.2473 155 CH 2

CH

2 OH 530.2336 156 562.2338 157 F 3 C 612.2349 0 5 - 141 - WO 2004/092166 PCT/US2004/010851 EXAMPLE 158 F F F 0 N O "INH N NH N N -\ N 5 N-[(3R,6S)-6-Phenyl-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yll-4-(8-oxo-8,9-dihydro-7H-purin 7-yl)piperidine- I -carbox amide Prepared essentially following the procedure outlined for the preparation of Example 146. MS 532.2250 (M+1). 10 EXAMPLE 159 F F 0 N 0 HN N N 4-(2-oxo-2,3-dihydro-IH-imidazof4,5-blpyrazin-1-yl)-N-[(3R,6S)-2-oxo-6-phenyl-1-(2,2,2 15 trifluoroethyl)azepan-3-yllpi peridine-1-carboxamide Prepared essentially following the procedure outlined for the preparation of Example 146. MS 532.2292 (M+1). 20 - 142 - WO 2004/092166 PCT/US2004/010851 EXAMPLE 160 0/ 0 N O N, 'NH NH 0 N F N 5 N-[(3R,6S)-6-(2,3-Difluorophenyl)-1-(2-methoxyethyl)-2-oxoazepan-3-yll-4-(6-oxo-6,7-dihydro 5H-imidazof4,5-clpyridazin-5-yl)piperidine- 1 -carboxamide Prepared essentially following the procedure outlined for the preparation of Example 146. MS 544.2465 (M+1). 10 EXAMPLE 161 / 0 N 0 N '"NH NH F N N N F N-[(3R,6S)-6-(2,3-Difluorophenyl)-1-(2-methoxvethyl)-2-oxoazepan-3-yll-4-(2-oxo-1,4 15 dihydropyrido[3,4-dlpyrimidin-3(2H)-yl)piperidine-I -carboxamide Prepared essentially following the procedure outlined for the preparation of Example 146. MS 557.2645 20 - 143 - WO 2004/092166 PCT/US2004/010851 EXAMPLE 162 / 0 NN N "oNH N H F N N F 5 N- [(3R,6S)-6-(2,3-Difluorophenyl)- 1-(2-methoxyethyl)-2-oxoazepan-3-yll -4-(2-oxo- 1,4 dihydropyridor4,3-d pyrimidin-3 (2H)-yl)piperidine- 1-carboxamide Prepared essentially following the procedure outlined for the preparation of Example 146 MS 557.2683 10 EXAMPLE 163 0 .N 0 N -"NH NH F N N N 0 F F N-[(3R,6S)-6-(2,3-Difluorophenyl)-1-(2-methoxyethyl)-2-oxoazepan-3-yll-4-(2-oxo-1,4 15 dihydropyrido[2,3-dlpyrimidin-3(2H)-yI)piperidine- 1-carboxamide Prepared essentially following the procedure outlined for the preparation of Example 146. MS 557.2701 20 - 144- WO 2004/092166 PCT/US2004/010851 EXAMPLE 164 F F F 0 N 0 F ON F OMe 5 N-[(3R,6S)-6-(2,3-Difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yll-4-(5-methoxy-2 oxo-2,3-dihydro-1H-imidazof4,5-blpyridin- I -yl)piperidine- 1 -carboxamide Prepared essentially following the procedure outlined for the preparation of Example 146. MS 597.2228 (M+1). 10 EXAMPLE 165 OH 0 N 0 "' NH )WNH 0 N F. F F N-[(3R,6S)-6-(2,3-Difluorophenyl)-1-(2-hydroxy-2-methylpropyl)-2-oxoazepan-3-yll-4-(6 15 fluoro-2-oxo-2,3-dihydro- IH-imidazo[4,5-blpyridin-1 -yl)piperidine-1 -carboxamide Prepared essentially following the procedure outlined for the preparation of Example 146. MS 575.2584 (M+1). 20 - 145 - WO 2004/092166 PCT/US2004/010851 EXAMPLE 166 F F F 0 N o N N F 5 N-[(3R,6S)-6-(2,3-Difluorophenvl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yll-4-(4-oxido-2-oxo 2,3-dihydro-IH-imidazo[4,5-blpyridin-1-yl)piperidine-1-carboxamide Prepared essentially following the procedure outlined for the preparation of Example 146. MS 583.2076 (M+1). 10 EXAMPLE 167 0 N 0 "'NH N NH O-

N

F N-[(3R,6S)-6-(2,3-Difluorophenyl)-1-methyl-2-oxoazepan-3-yll-4-(4-oxido-2-oxo-2,3-dihydro 15 IH-imidazo[4,5-blpyridin-1-yl)piperidine-1-carboxamide Prepared essentially following the procedure outlined for the preparation of Example 146. MS 515.2205 (M+1). 20 - 146 - WO 2004/092166 PCT/US2004/010851 EXAMPLE 168 0 NO "NH N N N N CN F CNr F 5 Step A. Phenyl N-cyano-N-[(3R,6S)-6-(2,3-difluorophenyl)-1-ethyl-2-oxoazepan-3 yllimidocarbamate. A solution of (3R,6S)-3-amino-6-(2,3-difluorophenyl)-1-ethylazepan-2-one (135 mg, 0.503 mmol) in dichloromethane was treated NN-diisopropylethylamine (65 mg, 0.503 mmol) and diphenyl N-cyanocarbonimidate (204 mg, 0.855 mmol). After 5 h, the reaction was 10 quenched with 0.5N NaOH and the organic layer washed with water and brine. The combined aqueous layers were extracted with EtOAc. The combined organics were dried, filtered and concentrated. Purification by silica gel chromatography (EtOAc / hexanes) gave the title compound (166 mg). MS 413.3 (M+1). 15 Step B. NV-Cyano-N-r(3R,6S)-6-(2,3-difluorophenyl)- I -ethyl-2-oxoazepan-3-yll-4-(2-oxo-2,3 dihydro- 1H-imidazof4,5-blpyridin- I -yl)piperidine- 1 -carboximidamide A solution of phenyl N'-cyano-N-[(3R,6S)-6-(2,3-difluorophenyl)- I -ethyl-2 oxoazepan-3-yllimidocarbamate (166 mg, 0.402 mmol) and 2-oxo-1-(4-piperidinyl)-2,3-dihydro 1H-imidazo[4,5-b]pyridine dihydrochloride (116 mg, 0.402 mmol), in 1-pentanol (10 mL) was 20 treated with NN-diisopropylethylamine (52 mg, 0.402 mmol). This mixture was heated to reflux for 24 h. Concentration and purification by silica gel chromatography (0% -> 10% methanol / dichloromethane) followed by reverse phase HPLC (C-18, 95% water/ acetonitrile -- 5% water/ acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (10 mg). MS 537.5 (M+1). 25 - 147 - WO 2004/092166 PCT/US2004/010851 EXAMPLE 169 OH H 0 N 0 '"NH kNH O ND N NH1 N N F F 5 N-[(3R,6S)-6-(2,3-Difluorophenyl)-7-(hydroxymethyl)-2-oxoazepan-3-yll-4-(2-oxo-2,3-dihydro 1H-imidazo[4,5-blpyridin-1-yl)piperidine-1-carboxamide Step A. Benzyl (2R,5S)-2-[bis(tert-butoxycarbonyl)aminol-5-(2,3-difluorophenyl)-7-hydroxy-6 nitroheptanoate 10 To a solution of (5S)-NN-bis(tert-butoxycarbonyl)-5-(2,3-difluorophenyl)-6-nitro D-norleucinate (2.30 g, 3.975 mmol) and 1,1,3,3-tetramethylguanidine (46 mg, 0.40 mmol) in acetonitrile (20 mL) was added formaldehyde (0.15 mL, 37% aqueous solution). After stirring for 60 min, more formaldehyde (0.050 mL, 37% aqueous solution) was added. After stirring for an additional 60 min the mixture was diluted with saturated aqueous NaHCO 3 and extracted with 15 CH 2 Cl 2 (3x). The combined organics were dried over magnesium sulfate, filtered and concentrated to give a residue that was purified by silica gel chromatography (25% -+ 75% ethyl acetate/ hexanes) to give the title compound (1.44 g,). MS 409.1 (M+1 - 2Boc). Step B. (5S)-N 2

,N

2 -bis(tert-Butoxycarbonyl)-5-(2,3-difluorophenyl)-6-(hydroxymethyl)-D-lysine 20 A solution of benzyl (2R,5S)-2-[bis(tert-butoxycarbonyl)amino]-5-(2,3 difluorophenyl)-7-hydroxy-6-nitroheptanoate (180 mg, 0.49 mmol) and 10% Pd/C (300 mg) in EtOH (5 mL, SureSeal from Aldrich), was hydrogenated at 55 psi for 7 d (200 mg more Pd/C was added after 3 d). The reaction was filtered through Celite with more EtOH and concentrated to afford the title compound (180 mg). MS 489.1 (M+1). 25 Step C. Di-tert-butyl [(3R,6S)-6-(2,3-difluorophenyl)-7-(hydroxymethyl)-2-oxoazepan-3 yllimidodicarbonate To a solution (5S)-N 2,N2-bis(tert-butoxycarbonyl)-5-(2,3-difluorophenyl)-6 (hydroxymethyl)-D-lysine (180 mg, 0.37 mmol) in DCM (5 mL) were added EDC (106 mg, 0.55 - 148 - WO 2004/092166 PCT/US2004/010851 mmol) and HOAT (50 mg, 0.37 mmol). After 30 min, NaHCO 3 was added, the layers separated and the aqueous phase backwashed with DCM. The combined organics were dried over magnesium sulfate, filtered and concentrated and the residue purified by silica gel chromatography (0% -> 10% MeOH/ DCM) to give the title compound (100 mg). MS 471.1 5 (M+1). Step D. (3R,6S)-3-amino-6-(2,3-difluorophenyl)-7-(hydroxymethyl)azepan-2-one Di-tert-butyl [(3R,6S)-6-(2,3-difluorophenyl)-7-(hydroxymethyl)-2-oxoazepan-3 yl]imidodicarbonate (100 mg, 0.213 mmol) was diluted DCM (30 mL) and TFA (8 mL) was 10 added. After 2 h, the reaction was concentrated to give the title compound as its TFA salt (57 mg). MS 271.0 (M+1). Step E. N-[(3R,6S)-6-(2,3-difluorophenyl)-7-(hydroxymethyl)-2-oxoazepan-3-yll-4-(2-oxo-2,3 dihydro- 1H-imidazo[4,5 -b]pyridin- I -yl)piperidine- 1 -carboxami de 15 Triethylamine (0. 68 mL, 0.49 mmol) was added to a solution of (3R,6S)-3 amino-6-(2,3-difluorophenyl)-7-(hydroxymethyl)azepan-2-one (57 mg, 0.21 mmol) and 4 nitrophenyl chloroformate (47 mg, 0.23 mmol) in tetrahydrofuran (10 mL) at 0 'C. After 30 min, 2-oxo- 1 -(4-piperidinyl)-2,3-dihydro- 1 H-imidazo[4,5-b]pyridine dihydrochloride (98 mg, 0.34 mmol), triethylamine (0.84 mmol) and chloroform (10 mL) were added and the mixture allowed 20 to warm to ambient temperature. The reaction was stirred overnight, concentrated, diluted with saturated aqueous sodium bicarbonate and extracted with dichloromethane (2x). The organic layer was washed with water, saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (1% -+ 12% methanol / dichloromethane) gave the title compound (17 mg). MS 515.2203 (M+1). 25 30 - 149 - WO 2004/092166 PCT/US2004/010851 EXAMPLE 170 OMe NO NH 0 F O N N NH F N 5 N-[5-(2,3-Difluorophenyl)-1-(2-methoxyethyl)-2-oxopiperidin-3-yll-4-(2-oxo-2,3-dihydro-IH imidazof4,5-blpyridin- I -y)piperidine- 1 -carboxamide Step A. 5-Bromo-1-(2-methoxyethyl)-3-nitropyridin-2(1H)-one Cesium carbonate (14.88 g, 45.66 mmol) was added to a solution of 5-bromo-3 nitropyridin-2-ol (10.0 g, 45.7 mmol) and 2-bromoethyl methyl ether (4.29 mL, 45.66 mmol) in 10 NN-dimethylformamide (400 mL). After 3 h, additional 2-bromoethyl methyl ether (4.29 mL, 45.7 mmol) was added, and the reaction was heated to 60 *C. After 4 h, water was added. The mixture was extracted with ethyl acetate (3x), and the combined organic extracts were washed with saturated brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes --+ 40% ethyl acetate/ hexanes) gave the title compound 15 (7.39 g). MS 277 (M). Step B. 5-(2,3-Difluorophenyl)- 1 -(2-methoxyethyl)-3-nitropyridin-2(1H)-one Palladium acetate (41.0 mg, 0.18 mmol) was added to a solution of 5-bromo-1-(2 methoxyethyl)-3-nitropyridin-2(IH)-one (500 mg, 1.81 mmol), 2,3-difluorophenyl boronic acid 20 (570 mg, 3.61 mmol), diisopropylamine (0.759 mL, 5.41 mmol) and 3,3',3" phosphinidynetris(benzenesulfonic acid) trisodium salt (310 mg, 0.541 mmol), in N,N dimethylformamide (15 mL) and water (5 mL) and heated to 80 4C. After 2 h, the mixture was allowed to cool to ambient temperature and filtered. Purification by reverse phase HPLC (C-18, 95% water/ acetonitrile -- 5% water/ acetonitrile with 0.1% trifluoroacetic acid) gave the title 25 compound (335mg). MS 311 (M+1). 'H NMR (500 MHz, CDCl 3 ) 8 8.56 (d, J = 2.7 Hz, 1H), - 150 - WO 2004/092166 PCT/US2004/010851 8.03 (d, J= 2.4 Hz, 1H), 7.23-7.18 (m, 2H), 7.15-7.12 (m, 1H), 4.33 (t, J= 4.8 Hz, 2H), 3.74 (t, J = 4.8 Hz, 2H), 3.35 (s, 3H). Step C. 3-Amino-5-(2,3-difluorophenyl)-1-(2-methoxyethyl)piperridin-2-one 5 10% Platinum on carbon (320 mg) was added to a solution of 5-(2,3 difluorophenyl)-1-(2-methoxyethyl)-3-nitropyridin-2(1H)-one (300 mg, 0.967 mmol) in acetic acid (10 mL). The reaction vessel was evacuated and back-filled with nitrogen (3x), then back filled with hydrogen (56 psi). After 65 h, the mixture was filtered and concentrated. MS 285 (M+1). 10 Step D. N-[5-(2,3-Difluorophenyl)-1-(2-methoxyethyl)-2-oxopiperidin-3-yll-4-(2-oxo-2,3 dihydro- 1H-imidazo[4.5-blpyridin-1 -yl)piperidine- 1 -carboxamide Triethylamine (83 pL, 0.598 mmol) was added to a solution of 3-amino-5-(2,3 difluorophenyl)-1-(2-methoxyethyl)piperidin-2-one (170 mg, 0.598 mmol) and 4 15 nitrophenylchloroformate (121 mg, 0.598 mmol) in tetrahydrofuran (4 mL) at 0 'C. After I h, 2 oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-blpyridine dihydrochloride (174 mg, 0.651 mmol), triethylamine (249 pL, 1.794 mmol) were added and the mixture allowed to warm to ambient temperature. After 18 h, saturated aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous 20 sodium bicarbonate (3x), saturated brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography [100% dichloromethane -+ 95% dichloromethane/ 5% (10% ammonium hydroxide/ methanol)] gave the title compound (0.135 g). MS 529.2353 (M+1). 'H NMR (500 MHz, CDCl 3 ) 5 8.03 (dd, J = 5.3, 1.1 Hz, 1H), 7.38 (dd, J = 7.8, 1.2 Hz, 1H), 7.11-7.03 (m, 2H), 7.01-6.96 (m, 2H), 5.82 (d, J= 3.4 Hz, 1H), 4.58-4.53 (m, 1H), 4.34 25 4.30 (m, 1H), 4.23 (d, J= 6.6 Hz, 2H), 3.71-3.62 (m, 3H), 3.60-3.53 (m, 311), 3.52-3.46 (m, IH), 3.33 (s, 3H), 2.96 (dd, J = 23.4, 10.5 Hz, 2H), 2.80-2.78 (m, 111), 2.28-2.21 (m, 2H), 1.90 (dd, J 10.5, 2.0 Hz, 211). 30 - 151 - WO 2004/092166 PCT/US2004/010851 Essentially following the procedures outlined for the preparation of Example 170, the Examples in Table E-6 were prepared. R1 N O R 2NH O N N NH N 5 TABLE E-6 Examples C-3 C-5 R R2 MS (M+1) 171 R or S R or S CH 2

CH

2 0CH 3 _ 493.2519 172 R or S R or S CH 3 _ 449.2285 173 R or S R or S CH 3 _ 485.2098 F F 174 R or S R or S CH 2

CF

3 _ 517.2154 175 R or S R or S CH 2

CF

3 553.1962 ___ F F 176 R R CH 2

CF

3 _ 517 - 152 - WO 2004/092166 PCT/US2004/010851 177 R S CH 2

CF

3 517 178 S R CH 2

CF

3 517 179 S S CH 2

CF

3 517 EXAMPLE 180 F3CO N O LNH N N hNN N NH O N F 5 F N-fl-(2,3-Difluorobenzyl)-5-oxo-4-(22.2-trifluoroethyl)-1,4-diazepan-6-yll-4-(2-oxo-2, 3 dihydro-1H-imidazo[4,5-blpyridin-1-yl)piperidine-1-carboxamide Step A: Benzyl 6-F(tert-butoxycarbonyl)aminol-5-oxo-1,4-diazepane-1-carboxylate 10 Triethylamine (0.56 mL, 3.99 mmol) was added to a solution of benzyl 6-amino 5-oxo-1,4-diazepane-1-carboxylate (1.05 g, 3.99 mmol) and di-tert-butyl dicarbonate (1.31 g, 6.00 mmol) in dichloromethane (30 mL). After 18 h, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% 15 dichloromethane --> 95% dichloromethane/ methanol) gave the title compound (1.35 g). MS 364 (M+ 1). Step B: Benzyl 6-[(tert-butoxycarbonyl)aminol-5-oxo-4-(2,2,2-trifluoroethyl)-1,4-diazepane-1 carboxylate - 153 - WO 2004/092166 PCT/US2004/010851 Sodium hydride (60% dispersion in mineral oil; 180 mg, 4.43 mmol) was added to a solution of benzyl 6-[(tert-butoxycarbonyl)amino]-5-oxo- 1,4-diazepane- I -carboxylate (1.34 g, 3.69 mmol) in N,N-dimethylformamide (25 mL) at -35*C. After 15 min, 2,2,2-trifluoroethyl trichloromethanesulfonate (0.911 mL, 5.54 mmol) was added and the reaction was stirred at -35 5 *C. After 2 h, an additional amount of sodium hydride (100 mg, 2.5 mmol) and trichloromethanesulfonate (0.500 mL, 3.04 mmol) were added. After 18 h, the reaction was quenched with water and the mixture was extracted with ethyl acetate. The organic layer was washed with water (3x), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (hexanes -+ 30% ethyl acetate/ hexanes) gave the title 10 compound (690 mg). MS 446 (M+1). Step C: tert-Butyl 7-oxo-1-(2,2,2-trifluoroethyl)-1,4-diazepan-6-ylcarbamate 10% Palladium on carbon (77 mg) was added to a solution of benzyl 6-[(tert butoxycarbonyl)amino] -5-oxo-4-(2,2,2-trifluoroethyl)- 1,4-diazepane- 1 -carboxylate (590 mg, 15 1.32 mmol) in ethanol (20 mL). The reaction vessel was evacuated and back-filled with nitrogen (3x), then back-filled with hydrogen (1 atm). After 18 h, the mixture was filtered and concentrated to give, the title compound (420 mg). MS 312 (M+1). 'H NMR (500 MHz, CDCl 3 ) 8 5.83 (s, 1H), 4.53-4.49 (m, IH), 4.29-4.20 (m, 1H), 3.96-3.88 (m, IH), 3.81-3.77 (m, 1H), 3.38 (d, J= 15.6 Hz, 1H), 3.26 (d, J= 12.9 Hz, 1H), 3.16-3.13 (m, IH), 2.81-2.79 (m, 1H), 2.72-2.67 20 (m, 1H), 1.83 (br s, IH), 1.45 (s, 9H). Step D. tert-Butyl 1-(2,3-difluorobenzyl)-5-oxo-4-(2,2,2-trifluoroethyl)-1,4-diazepan-6 ylcarbamate A mixture of tert-butyl 7-oxo-1-(2,2,2-trifluoroethyl)-1,4-diazepan-6-ylcarbamate 25 (51 mg, 0.16 mmol), 2,3-difluorobenzaldehyde (0.053 mL, 0.49 mmol), and sodium cyanoborohydride (31 mg, 0.49 mmol) in methanol (5 mL) was adjusted to pH 4 with acetic acid. After 0.5 h, saturated aqueous sodium bicarbonate was added and the mixture was extracted with dichloromethane (3x). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. Purification by silica gel chromatography [100% dichloromethane -+ 30 95% dichloromethane/ 5% (10% ammonium hydroxide/ methanol)] gave the title compound (62 mg). MS 438 (M+ 1). - 154 - WO 2004/092166 PCT/US2004/010851 Step E: 6-Amino-I -(2,3-difluorobenzyl)-4-(2,2,2-trifluoroeth yl)- 1,4-diazepan-5-one Trifluoroacetic acid (2.5 mL) was added to a solution of tert-butyl 1-(2,3 difluorobenzyl)-5-oxo-4-(2,2,2-trifluoroethyl)- 1,4-diazepan-6-ylcarbamate (62 mg, 0.142 mmol) in dichloromethane (5 mL). After I h, the solution was concentrated. Saturated aqueous sodium 5 bicarbonate solution was added and the mixture was extracted with dichloromethane (3x). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated to give the title compound (45 mg). MS 338 (M+1). Step F: N-[1-(2,3-Difluorobenzyl)-5-oxo-4-(2,2,2-trifluoroethyl)-1,4-diazepan-6-yll-4-(2-oxo 10 2,3-dihydro-1H-imidazo[4,5-blpyridin-1-yl)piperidine-1-carboxamide Triethylamine (0.012 mL, 0.133 mmol) was added to a solution of 6-amino-1 (2,3-difluorobenzyl)-4-(2,2,2-trifluoroethyl)- 1,4-diazepan-5-one (45 mg, 0.133 mmol) and 4 nitrophenyl chloroformate (27 mg, 133 mmol) in tetrahydrofuran (2.5 mL) at 0 'C. After 1 h, 2 oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-bipyridine dihydrochloride (43 mg, 0.147 15 mmol) and triethylamine (0.048 mL, 0.532 mmol) were added and the mixture allowed to warm to ambient temperature. After 18 h, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with water (2x), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography [100% dichloromethane - 92% dichloromethane/ methanol (10% ammonium hydroxide/ methanol)] gave the title 20 compound (67 mg). MS 582.2262 (M+1). 'H NMR (500 MHz, CDCl 3 ) 8 8.77 (s, 1H), 8.03 (d, J= 5.4 Hz, 1H), 7.31 (d, J= 8.1 Hz, 1H), 7.27-7.24 (m, 1H), 7.09-7.05 (m, 2H), 6.98 (dd, J= 8.1, 5.4 Hz, 1H), 5.99 (d, J= 4.9 Hz, 1H), 4.91-4.88 (m, 1H), 4.57-4.50 (m, 1H), 4.25-4.16 (m, 3H), 4.00-3.92 (m, 2H), 3.84 (dd, J= 32.7, 14.2 Hz, 2H), 3.36-3.34 (m, IH), 3.20 (d, J = 12.5 Hz, 1H), 2.99-2.91 (m, 3H), 2.44-2.37 (m, 2H), 2.31-2.18 (m, 2H), 1.90 (d, J= 11.0 Hz, 2H). 25 Essentially following the procedures outlined for the preparation of Example 180, the Examples in Table E-7 were prepared. 30 - 155 - WO 2004/092166 PCT/US2004/010851 TABLE E-7

F

3 C NN NNH No Nt R2 O N 5 Example R 2 MS (M+1) 181 CH2 546.2450 182 H 456.1983 183 O 0 590.2295 - 156 -

Claims

1. A compound of the Formula I: R1 QU R 2 O R)1_ NQ- A W---N G NH R2 A BQ 5 1 wherein: A is a bond, C(R 2 )2, 0, S(O)m or NR 2 ; 10 B is (C(R 2 )2)n; R is selected from: 1) H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C6 alkynyl, C3-6 cycloalkyl, and heterocycle, 15 unsubstituted or substituted with one or more substituents independently selected from: a) Ct6alkyl, b) C36 cycloalkyl, c) aryl, unsubstituted or substituted with 1-5 substituents where 20 the substituents are independently selected from R 4 , d) heteroaryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , 25 f) (F)pCi-3 alkyl, g) halogen, h) OR 4 , i) 0(CH2)s OR 4 , j) C0 2 R 4 , 30 k) (CO)NR I R 1 1. - 157 - WO 2004/092166 PCT/US2004/010851 1) O(CO)NR 10 RI, m) N(R 4 )(CO)NR1ORI 1, n) N(R 1 )(CO)RI1, o) N(R 1 O)(CO)O R I1, 5 p) SO2NR' 0 RIl, q) N(R 1 0 ) SO2R1 1, r) S(O)mR 10 , s) CN, t) NRIORII, 10 u) N(RI0)(CO)NR 4 RII and, v) O(CO)R 4 ; 2) aryl or heteroaryl, unsubstituted or substituted with one or more substituents independently selected from: 15 a) Cl-6 alkyl, b) C3-6 cycloalkyl, c) aryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , d) heteroaryl, unsubstituted or substituted with 1-5 substituents 20 where the substituents are independently selected from R 4 , e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , f) (F)pCl-3 alkyl, g) halogen, 25 h) OR 4 , i) O(CH2)sOR 4 , j) C0 2 R 4 , k) (CO)NRIORil, 1) O(CO)NR 10 RIl, 30 m) N(R 4 )(CO)NR 1 ORI 1, n) N(RI)(CO)RI1, o) N(RIO)(CO)ORIl, p) SO2NR' 0 R 1 l, q) N(R1 0 ) SO2R11, - 158 - WO 2004/092166 PCT/US2004/010851 r) S(O)mR' 0 , s) CN, t) NRI0RII, u) N(RI 0)(CO)NR 4 R II and, 5 v) O(CO)R 4 ; 2 R is independently selected from: 1) H, CO-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C3-6 cycloalkyl and heterocycle, unsubstituted or substituted with one or more substituents independently selected 10 from: a) C-6 alkyl, b) C3-6 cycloalkyl, c) aryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , 15 d) heteroaryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , f) (F)pCl.3 alkyl, 20 g) halogen, h) OR 4 , i) O(CH2)sOR 4 j) C0 2 R 4 k) (CO)NR IOR 1 1, 25 1) O(CO)NR IOR 1 1 , m) N(R 4 )(CO)NRIORI 1, n) N(R 10 )(CO)R 11, o) N(RIO)(CO)ORI 1, p) SO2NRIOR"1, 30 q) N(R 1 0 ) S02R"1, r) S(O)mRI 0 , s) CN, t) NIRI u) N(RO)(CO)NR 4 RII and, - 159 - WO 2004/092166 PCT/US2004/010851 v) O(CO)R 4 ; 2) aryl or heteroaryl, unsubstituted or substituted with one or more substituents independently selected from: 5 a) C1-6 alkyl, b) C3-6 cycloalkyl, c) aryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , d) heteroaryl, unsubstituted or substituted with 1-5 substituents 10 where the substituents are independently selected from R 4 , e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , f) (F)pC 1-3 alkyl, g) halogen, 15 h) OR 4 , i) O(CH2)sOR 4 , j) CO 2 R 4 , k) (CO)NRIOR 1 i, 1) O(CO)NRIORII, 20 m) N(R 4 )(CO)NR 10 RI 1 , n) N(RI0)(CO)RI 1 , o) N(R 10 )(CO)O R 11, p) SO2NR' 0 RIl, q) N(R1 0 )SO2RI1, 25 r) S(O)mR 10 , s) CN, t) NR10Ril, u) N(R 10 )(CO)NR 4 R I and, v) O(CO)R 4 , 30 or, any two independent R 2 on the same or adjacent atoms may be joined together to form a ring selected from cyclobutyl, cyclopentenyl, cyclopentyl, cyclohexenyl, cyclohexyl, phenyl, naphthyl, thienyl, thiazolyl, thiazolinyl, oxazolyl, oxazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrimidyl, pyrazinyl, pyrrolyl, pyrrolinyl, - 160 - WO 2004/092166 PCT/US2004/010851 morpholinyl, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S-dioxide, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyndyl, furanyl, dihydrofuranyl, dihydropyranyl and piperazinyl; 5 R 10 and R 1 1 are independently selected from: H, C1-6 alkyl, (F)pC1-6 alkyl, C3-6 cycloalkyl, aryl, heteroaryl, and benzyl, unsubstituted or substituted with halogen, hydroxy or C1-C6 alkoxy, where R 10 and R 1 1 may be joined together to form a ring selected from: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 ; 10 R 4 is independently selected from: H, C1-6 alkyl, (F)pC1-6 alkyl, C 3 -6 cycloalkyl, aryl, heteroaryl and benzyl, unsubstituted or substituted with halogen, hydroxy or CI-C6 alkoxy; W is 0, NR 4 or C(R 4 )2; 15 X is C or S; Y is 0, (R 4 )2, NCN, NSO2CH3, NCONH2, or Y is 02 when X is S; 20 R 6 is independently selected from H and: a) C1-6 alkyl, b) C3-6 cycloalkyl, c) aryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , 25 d) heteroaryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , f) (F)pC13 alkyl, 30 g) halogen, h) QR 4 , i) 0(CH2)sOR 4 . j) C0 2 R 4 k) (CO)NRIORII 1 - 161 - WO 2004/092166 PCT/US2004/010851 I) O(CO)NR 1 ORI 1 , m) N(R 4 )(CO)NR 10 RII, n) N(R 10 )(CO)RIl, o) N(R 10 )(CO)OR I1, 5 p) SO2NR1 0 RIl, q) N(R10) S02R 1, r) S(O)mR 1 0 , s) CN, t) NRIORIl, 10 u) N(R 10 )(CO)NR 4 R 11 and, v) O(CO)R 4 ; G-J is selected from: N, N-C(R 5 )2, C=C(R 5 ), C=N; C(R 5 ), C(R5)-C(R 5 )2, C(R 5 )-C(R 5 )2 C(R 5 )2, C=C(R 5 )-C(R 5 )2, C(R 5 )-C(R 5 )=C(R 5 ), C(R 5 )-C(R 5 )2-N(R 5 ), C=C(R 5 )-N(R5), 15 C(R5)-C(R5)=N, C(R5)-N(R 5 )-C(R 5 )2, C=N-C(R 5 )2, C(R5)-N=C(R5), C(R 5 )-N(R 5 )-N(R 5 ), C=N-N(R 5 ), N-C(R 5 )2-C(R 5 )2, N-C(R 5 )=C(R 5 ), N-C(R 5 )2-N(R 5 ), N-C(R5)=N, N-N(R5) C(R 5 )2 and N-N=C(R 5 ); Q, T, U and V are each independently carbon or nitrogen wherein at least one but no more than 20 three of Q, T, U and V are nitrogen, of which one may be optionally an N-oxide, and wherein when any of Q, T, U, or V is carbon it is unsubstituted or substituted where the substituents are independently selected from R 6 ; R 5 is independently selected from H, substituted or unsubstituted C1-C3 alkyl, CN, OR 4 , 25 N(R 4 )2 and C0 2 R 4 ; R 3 is independently selected from H, substituted or unsubstituted CI-C3 alkyl, F, CN and C0 2 R 4 ; 30 p is 0 to 2q+1, for a substituent with q carbons; m is 0, 1 or 2; n is 0 or 1; s is 1, 2 or 3; - 162 - WO 2004/092166 PCT/US2004/010851 and pharmaceutically acceptable salts and individual diastereomers thereof. 5

2. The compound of claim 1 of the Formula la: R' Q- T- U R2 \ 0 (R 3 ) 19 " 2 A' W N G NH RY 0 Ia 10 wherein: A is a bond, C(R 2 )2, 0, S(O)m or NR 2 ; B is (C(R 2 )2)n; 15 Y is O or NCN; and n is 0 or I; and pharmaceutically acceptable salts and individual stereoisomers thereof.

3. The compound of claim 1 of the Formula Ib: 20 R1 Q*IT U 02 (R 3 ) I 9 R 2I W N U N H R2 0 0 Ib wherein: 25 A is a bond, C(R 2 )2, 0, S(O)m or NR 2 ; B is (C(R 2 )2)n; and - 163 - WO 2004/092166 PCT/US2004/010851 n is 0 or I; and pharmaceutically acceptable salts and individual stereoisomers thereof.

4. The compound of claim I of the Formula Ic: 5 0 U R N (R ) 1 _ 9 R NH R 2R N R O0 Ic and pharmaceutically acceptable salts and individual stereoisomers thereof. 10

5. The compound of claim I of the Formula Id: R1Q U R2 R2 R31_ Q R2 W - N G NH R2A R 4 G o 0 Id 15 wherein: A is C(R 2 )2, 0, S(O)m or NR 2 I and pharmaceutically acceptable salts and individual stereoisomers thereof.

6. The compound of claim 1 of the Formula le: 20 R1 Q ,T-U R2 0 (R') j. 9 R 2 N 2 W N G NH R 2 A R R2 0 0 le - 164 - WO 2004/092166 PCT/US2004/010851 wherein: A is C(R 2 )2, 0, S(O)m or NR 2 ; and pharmaceutically acceptable salts and individual stereoisomers thereof. 5

7. The compound of claim 1, wherein: R 1 is selected from: 1) H, CI-C 6 alkyl, C3-6 cycloalkyl and heterocycle, unsubstituted or substituted 10 with one or more substituents independently selected from: a) C1-6 alkyl, b) C3-6 cycloalkyl, c) aryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , 15 d) heteroaryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , f) (F)pC1-3 alkyl, 20 g) halogen, h) OR 4 , i) O(CH2)sOR 4 , j) C0 2 R 4 , k) CN, 25 1) NR 10 RI 1 , and m) O(CO)R 4 ; and 2) aryl or heteroaryl, unsubstituted or substituted with one or more substituents independently selected from: a) C1-6 alkyl, 30 b) C3-6 cycloalkyl, c) (F)pC1-3 alkyl, d) halogen, e) OR 4 . f) C0 2 R 4 , -165- WO 2004/092166 PCT/US2004/010851 g) (CO)NR 1 OR 11 , h) SO2NR1 0 RII, i) N(R 1 0 ) SO 2 RI1, j) S(O)mR 4 , 5 k) CN and 1) NR 10 R 1 1 , and m) O(CO)R4; and R 2 is selected from: 10 1) H, C 1 -C 6 alkyl, C2-C 6 alkynyl, C3-6 cycloalkyl and heterocycle, unsubstituted or substituted with one or more substituents independently selected from: a) C1-6 alkyl, b) C3-6 cycloalkyl, c) aryl, unsubstituted or substituted with 1-5 sustituents where the 15 substituents are independently selected from R 4 , d) heteroaryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , 20 f) (F)pC1-3 alkyl, g) halogen, h) OR 4 , i) O(CH 2 )sOR 4 , j) CO 2 R 4 , 25 k) S(O)mR 4 , 1) CN, m) NR 10 R 1 l, and n) O(CO)R 4 ; and 30 2) aryl or heteroaryl, unsubstituted or substituted with one more substituents independently selected from: a) C1-6 alkyl, b) C3-6 cycloalkyl, c) (F)pC1-3 alkyl, - 166 - WO 2004/092166 PCT/US2004/010851 d) halogen, e) OR 4 , f) CO 2 R 4 , g) (CO)NR 1 ORII, 5 h) SO2NRI 0 R 1 , i) N(R10) SO 2 R 1 1 , j) S(O)mR 4 , k) CN, 1) NR 10 R 1 , 10 m) O(CO)R 4 , or, any two independent R 2 on the same or adjacent atoms may be joined together to form a ring selected from cyclobutyl, cyclopentenyl, cyclopentyl, cyclohexenyl, cyclohexyl, phenyl, naphthyl, thienyl, thiazolyl, thiazolinyl, oxazolyl, oxazolinyl, imidazolyl, 15 imidazolinyl, imidazolidinyl, pyridyl, pyrimidyl, pyrazinyl, pyrrolyl, pyrrolinyl, morpholinyl, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S-dioxide, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridyl, furanyl, dihydrofuranyl, dihydropyranyl and piperazinyl; 20 G-J is selected from: N, N-C(R 5 )2, C=C(R 5 ), C=N, C=C(R5)-C(R5), C(R5)-C(R 5 )=C(R 5 ), N-C(R 5 )2-C(R 5 )2 and N-C(R5)=C(R5); 25 R 6 is independently selected from H and: a) C 1-6 alkyl, b) C3-6 cycloalkyl, c) (F)pC1-3 alkyl, d) halogen, 30 e) OR 4 , f) CO 2 R4, g) (CO)NR 10 RI 1 , h) S0 2 NR 1 0 R 11 , i) N(R 1 0 )SO 2 RI . - 167 - WO 2004/092166 PCT/US2004/010851 j) S(O)mR 4 , k) CN, 1) NR 10 R11, and m) O(CO)R 4 ; 5 and pharmaceutically acceptable salts and individual stereoisomers thereof.

8. The compound of claim 7 of the Formula Ia: R1 Q*-T U N R2O A---B RW N G NH 10 R 0 Ia wherein: 15 A is a bond, C(R 2 )2, 0, S(O)m or NR 2 ; B is (C(R 2 )2)n; Y is O or NCN; and n is 0 or 1; and pharmaceutically acceptable salts and individual stereoisomers thereof. 20

9. The compound of claim 7 of the Formula Ib: R1 Q,--1 U R 0 (RR) 9 R2 O NO R 2AVB R 4 0 0 0 Ib 25 wherein: A is a bond, C(R 2 )2, 0, S(O)m or NR 2 ; - 168 - WO 2004/092166 PCT/US2004/010851 B is (C(R 2 )2)n; and n is 0 or 1; and pharmaceutically acceptable salts and individual stereoisomers thereof. 5

10. The compound of claim 7 of the Formula Ic: 1 Q U R2R N 1 R 2 O 0W - N G N H R 2 R2R4 0 0 IC 10 and pharmaceutically acceptable salts and individual stereoisomers thereof.

11. The compound of claim 7 of the Formula Id: R4 Q* U R ( ) 1 9 N 0 NI) -9 i R2 A R 4 N G NH 15 0 0 Id wherein: A is C(R 2 )2, 0, S(O)m or NR 2 ; 20 and pharmaceutically acceptable salts and individual stereoisomers thereof.

12. The compound of claim 7 of the Formula le: - 169 - WO 2004/092166 PCT/US2004/010851 R1 Q,-T U R2\ 0 (R 3 ) 19 g N R2O A R4W N G NH R2 O O4 0 00 le wherein: 5 A is C(R 2 )2, 0, S(O)m or NR 2 ; and pharmaceutically acceptable salts and individual stereoisomers thereof.

13. The compound of claim 1, wherein: 10 R is selected from: 1) H, Ci-C 6 alkyl, C3-6 cycloalkyl and heterocycle, unsubstituted or substituted with one or more substituents independently selected from: a) C1-6 alkyl, b) C3-6 cycloalkyl, 15 c) phenyl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , d) heteroaryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , and where heteroaryl is selected from: 20 imidazole, isoxazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, and thiazole; e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , and where heterocycle is selected from: 25 azetidine, dioxane, dioxolane, morpholine, oxetane, piperazine, piperidine, pyrrolidine, tetrahydrofuran, and tetrahydropyran; f) (F)pCb3 alkyl, g) halogen, h) OR 4 30 i) O(CH 2 )OR4, - 170 - WO 2004/092166 PCT/US2004/010851 j) C0 2 R 4 , k) CN, and 1) NR10Ril; and 5 2) aryl or heteroaryl, selected from: phenyl, imidazole, isoxazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, and thiazole; unsubstituted or substituted with one or more substituents independently selected from: a) C1-6 alkyl, 10 b) C 3 -6 cycloalkyl, c) (F)pC1-3 alkyl, d) halogen, e) OR 4 , f) C0 2 R 4 , 15 g) (CO)NR 1 0 R 11 , h) SO 2 NR 10 R 11 , i) N(R 10) SO2R 11, j) S(O)mR 4 , k) CN and 20 1) NR1IRil; R 2 is selected from: 1) H, CO-C 6 alkyl, C3-6 cycloalkyl and heterocycle, unsubstituted or substituted with one or 25 more substituents independently selected from: a) C1-6 alkyl, b) C3-6 cycloalkyl, c) phenyl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , 30 d) heteroaryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , and where heteroaryl is selected from: - 171 - WO 2004/092166 PCT/US2004/010851 benzimidazole, benzothiophene, furan, imidazole, indole, isoxazole, oxazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, and triazole; e) heterocycle, unsubstituted or substituted with 1-5 substituents 5 where the substituents are independently selected from R 4 , and where heterocycle is selected from: azetidine, imidazolidine, imidazoline, isoxazoline, isoxazolidine, morpholine, oxazoline, oxazolidine, oxetane, pyrazolidine, pyrazoline, pyrroline, tetrahydrofuran, tetrahydropyran, thiazoline, 10 and thiazolidine; f) (F)pCl-3 alkyl, g) halogen, h) OR 4 , i) O(CH)OR 4 15 j) CO 2 R 4 , k) CN, and 1) NRIORI 1 ; and 2) aryl or heteroaryl, selected from: 20 phenyl, benzimidazole, benzothiophene, furan, imidazole, indole, isoxazole, oxazole, pyrazine, pyrazole, pyndazine, pyridine, pyrimidine, pyrrole, thiazole, thiophene, and triiazole; unsubstituted or substituted with one or more substituents independently selected from: 25 a) C1-6alkyl, b) C36 cycloalkyl, c) (F)pCl-3 alkyl, d) halogen, e) OR 4 , 30 f) CO 2 R 4 , g) (CO)NR I O; a 1 h) So2NRoR i) N(R1 0 ) S02R. j) S(O)mR 4 , - 172 - WO 2004/092166 PCT/US2004/010851 k) CN and 1) NRI0R 11, or, any two independent R2 on the same or adjacent atoms may be joined together to form 5 a ring selected from cyclobutyl, cyclopentenyl, cyclopentyl, cyclohexenyl, cyclohexyl, phenyl, naphthyl, thienyl, thiazolyl, thiazolinyl, oxazolyl, oxazolinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, pyrimidyl, pyrazinyl, pyrrolyl, pyrrolinyl, morpholinyl, thiomorpholine, thiomorpholine S-oxide, thiomorpholine S-dioxide, azetidinyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, 10 tetrahydropyridyl, furanyl, dihydrofuranyl, dihydropyranyl and piperazinyl; R 10 and R Ii are independently selected from: H, C1-6 alkyl, (F)pC1-6 alkyl, C3-6 cycloalkyl, aryl, heteroaryl and benzyl, unsubstituted or substituted with halogen, hydroxy or C1-C6 alkoxy, where RIO and R11 may be joined together to form a ring selected from: azetidinyl, pyrrolidinyl, 15 piperidinyl, piperazinyl and morpholinyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 ; R 4 is independently selected from: H, C1-6 alkyl, (F)pC1-6 alkyl, C3-6 cycloalkyl, aryl-, heteroaryl and phenyl, unsubstituted or substituted with hydroxy or C1-C6 alkoxy; 20 W is NR 4 or C(R 4 )2; G-J is N and Q-T-U-V is N=C(R 6 )-C(R 6 )=C(R 6 ), G-J is N and Q-T-U-V is C(R 6 )=N C(R 6 )=C(R 6 ), G-J is N and Q-T-U-V is C(R 6 )=C(R 6 )-N=C(R 6 ), 25 G-J is N and Q-T-U-V is C(R 6 )=C(R 6 )-C(R 6 )=N, G-J is N and Q-T-U-V is C(R 6 )=C(R 6 )-N=N, G-J is N and Q-T-U-V is C(R 6 )=N-C(R 6 )=N, G-J is N and Q-T-U-V is N=C(R 6 )-C(R 6 )=N, G-J is N-C(R 5 )2 and Q-T-U-V is C(R 6 )=C(R 6 )-C(R 6 )=N, G-J is N-C(R 5 )2 and Q-T-U-V is C(R 6 )=N-C(R 6 )=C(R 6 ), G-J is C=C(R 5 ) and Q-T-U-V is C(R 6 )=C(R 6 )-C(R 6 )=N, G-J is C=C(R 5 ) and Q-T-U-V is C(R 6 )=N-C(R 6 )=C(R 6 ), G-J is C=N and Q-T-U-V is C(R 6 )=C(R 6 ) 30 C(R 6 )=N, G-J is C=N and Q-T-U-V is C(R 6 )=N-C(R 6 )=C(R 6 ), G-J is N-C(R 5 )2-C(R5)2 and Q T-U-V is C(R 6 )=C(R 6 )-C(R 6 )=N, or G-J is N-C(R 5 )2-C(R5) 2 and Q-T-U-V is C(R 6 )=N C(R 6 )=C(R 6 ). - 173 - WO 2004/092166 PCT/US2004/010851 R 6 is independently selected from H and: a) C1-6 alkyl, b) C3-6 cycloalkyl, c) (F)pCl-3 alkyl, 5 d) halogen, e) OR 4 , f) C0 2 R 4 , g) (CO)NR 10 RII, h) S0 2 NR 10 R 1 1 , 10 i) N(R1 0 ) S0 2 R 11 . j) S(O)mR 4 , k) CN and 1) NRIORIl; 15 and pharmaceutically acceptable salts and individual stereoisomers thereof.

14. The compound of claim 13 of the Formula Ia: R1 QJ- U 2 \ 0 (R3) N 2 A.-- RW N G NH 2 - R 4 YI RY 0 20 la and pharmaceutically acceptable salts and individual stereoisomers thereof.

15. The compound of claim 13 of the Formula Ib: 25 R1 Q1'T U 0 (R') 1 - 9 NY R2 W N H A- B R R 0 O - 174 - WO 2004/092166 PCT/US2004/010851 Ib and pharmaceutically acceptable salts and individual stereoisomers thereof.

16. The compound of claim 13 of the Formula Ic: 5 - U R2 R O(R WY U NH R 2 2R R R 2 O o 0 Ic and pharmaceutically acceptable salts and individual stereoisomers thereof. 10

17. The compound of claim 13 of the Formula Id: R1 015 UT 2R 2 3) R 2 N (R 3 _ 9 R 2 - W N G NH R2A R 4 o 0 Id 15 and pharmaceutically acceptable salts and individual stereoisomers thereof.

18. The compound of claim 13 of the Formula le: R1 QJ U R2\ o R )_ RW N GYNH 20 R 0 0 le - 175 - WO 2004/092166 PCT/US2004/010851 and pharmaceutically acceptable salts and individual stereoisomers thereof.

19. A compound of the Formula II: R1 Q U N 2 B G NH R2 5 II wherein: B is independently (C(R 2 )2)n; 10 R is selected from: 1) H, CI-C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C3-6 cycloalkyl, and heterocycle, unsubstituted or substituted with one or more substituents independently selected 15 from: a) C1-6 alkyl, b) C3-6 cycloalkyl, c) aryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , 20 d) heteroaryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , f) (F)pC1-3 alkyl, 25 g) halogen, h) OR 4 , i) O(CH2)s OR 4 , j) C0 2 R 4 , k) (CO)NRIOR11, -176- WO 2004/092166 PCT/US2004/010851 1) O(CO)NR 10 R 11 , m) N(R 4 )(CO)NR 10 RI1, n) N(RI 0 )(CO)RII, o) N(RIO)(CO)ORI 1, 5 p) SO2NR1 0 RI1, q) N(R1) SO 2 R11, r) S(O)mR 10 , s) CN, t) NR10R 1, and 10 u) N(R 10 )(CO)NR 4 R 11; and, 2) aryl or heteroaryl, unsubstituted or substituted with one or more substituents independently selected from: a) C1-6 alkyl, 15 b) C3-6 cycloalkyl, c) aryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , d) heteroaryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , 20 e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , f) (F)pC 1-3 alkyl, g) halogen, h) OR 4 , 25 i) O(CH2)sOR 4 , j) C0 2 R 4 , k) (CO)NR 10 R 1 1 , 1) O(CO)NR 1 ORI 1 , m) N(R4)(CO)NR 10Ril, 30 n) N(R 10 )(CO)RI 1, o) N(RIO)(CO)OR 11, p) SO2NR' 0 RIl, q) N(R1 0 ) SO2R11, r) S(O)mR' 0 , - 177 - WO 2004/092166 PCT/US2004/010851 s) CN, w) NR 10 R 11 , and x) N(R 10 )(CO)NR 4 RII; 2 5 R is independently selected from: 1) H, CO-C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C3-6 cycloalkyl and heterocycle, unsubstituted or substituted with one or more substituents independently selected from: a) C1-6 alkyl, 10 b) C3-6 cycloalkyl, c) aryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , d) heteroaryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from 15 R4, e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R4, f) (F)pC1-3 alkyl, 20 g) halogen, h) OR 4 , i) O(CH2)sOR 4 . j) C0 2 R 4 , k) (CO)NR 10 R 1 1, 25 1) O(CO)NR 1 ORIl, m) N(R 4 )(CO)NR 1 ORI 1, n) N(RIO)(CO)RI 1, o) N(R 10 )(CO)ORI1, p) S02NR 10 RIl, 30 q) N(R 10 ) S02R 11, r) S(O)mR1 0 , s) CN, t) NR 1 0 R 11 , and u) N(R 1 0 )(CO)NR 4 RI 1; and, - 178 - WO 2004/092166 PCT/US2004/010851 2) aryl or heteroaryl, unsubstituted or substituted with one or more substituents independently selected from: 5 a) C1-6 alkyl, b) C3-6 cycloalkyl, c) aryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , d) heteroaryl, unsubstituted or substituted with 1-5 substituents 10 where the substituents are independently selected from R 4 , e) heterocycle, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , f) (F)pC1-3 alkyl, g) halogen, 15 h) OR 4 , i) O(CH2)sOR 4 , j) C0 2 R 4 , k) (CO)NR 10 R 1 l, 1) O(CO)NR1 0 R 1 l, 20 m) N(R 4 )(CO)NR1 0 RI1. n) N(R 10 )(CO)R 11 , o) N(R 1 )(CO)ORIl, p) SO2NR1 0 RI", q) N(R1 0 ) SO2RI I, 25 r) S(O)mR1 0 , s) CN, t) NR1 0 R 1 1 , and u) N(R1O)(CO)NR 4 Rl; 30 RIO and RI I are independently selected from: H, C1-6 alkyl, (F)pC1-6 alkyl, C3-6 cycloalkyl, aryl, heteroaryl, and benzyl, unsubstituted or substituted with halogen, hydroxy or C1-C6 alkoxy, where R 10 and RI I may be joined together to form a ring selected from: azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl, which is unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 - 179 - WO 2004/092166 PCT/US2004/010851 R 4 is independently selected from: H, C1-6 alkyl, (F)pCl-6 alkyl, C3-6 cycloalkyl, aryl, heteroaryl and benzyl, unsubstituted or substituted with halogen, hydroxy or C 1 -C6 alkoxy; 5 W is 0, NR 4 or C(R 4 )2; X is C or S; Y is 0, (R 4 )2, NCN, NSO2CH3, NCONH2, or Y is 02 when X is S; 10 R 6 is independently selected from H and: a) Cl-6 alkyl, b) C3-6 cycloalkyl, 15 c) aryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , d) heteroaryl, unsubstituted or substituted with 1-5 substituents where the substituents are independently selected from R 4 , e) heterocycle, unsubstituted or substituted with 1-5 substituents 20 where the substituents are independently selected from R 4 , f) (F)pCI-3 alkyl, g) halogen, h) OR 4 , i) O(CH2)sOR 4 , 25 j) C0 2 R 4 , k) (CO)NR 1 OR 1 1 , 1) O(CO)NRIOR"I, m) N(R 4 )(CO)NR 10 RI I, n) N(R 10 )(CO)RI 1 , 30 o) N(R10)(CO)OR 1 . p) SO2NR' 0 RI", q) N(R 10) SO2RI 1, r) S(O)mR 1 0 , s) CN, -180- WO 2004/092166 PCT/US2004/010851 t) NR10RII, and u) N(R1O)(CO)NR 4 R11; G-J is selected from: N, N-C(R 5 )2, C=C(R 5 ), C=N; C(R 5 ), C(R 5 )-C(R 5 )2, C(R 5 )-C(R 5 )2 5 C(R 5 )2, C=C(R 5 )-C(R 5 )2, C(R 5 )-C(R 5 )=C(R 5 ), C(R 5 )-C(R 5 )2-N(R 5 ), C=C(R 5 )-N(R5), C(R5)-C(R 5 )=N, C(R 5 )-N(R 5 )-C(R 5 )2, C=N-C(R 5 )2, C(R 5 )-N=C(R 5 ), C(R5)-N(R5)-N(R5), C=N-N(R 5 ), N-C(R 5 )2-C(R 5 )2, N-C(R5)=C(R5), N-C(R 5 )2-N(R 5 ), N-C(R5)=N, N-N(R5) C(R 5 )2 and N-N=C(R 5 ); 10 Q, T, U and V are each independently carbon or nitrogen wherein at least one but no more than three of Q, T, U and V are nitrogen, and wherein when any of Q, T, U, or V is carbon it is unsubstituted or substituted where the substituents are independently selected from R 6 ; R 5 is independently selected from H, substituted or unsubstituted Cl-C3 alkyl, CN, OR 4 , 15 N(R 4 )2 and C0 2 R 4 ; R 3 is independently selected from H, substituted or unsubstituted C1-C3 alkyl, F, CN and C0 2 R 4 ; 20 p is 0 to 2q+1, for a substituent with q carbons; m is 0, 1 or 2; n is 0 or 1; s is 1, 2 or 3; 25 and pharmaceutically acceptable salts and individual diastereomers thereof. - 181 - WO 2004/092166 PCT/US200-I/010851

20. A compound selected from: MeO HO0 0 N0 N .IHIHN-N %-NH ''NH N N o 0 N 0N 0 ""IN N_ N H INH H-N 0N Nx 0 N CF 3 (0 oC, N 0 N JN 0 ".INH N o 0 - N I0 N NF F MeO Me0 O 0 N 0N0 "1 No N N H -- III ' " ND N NH 0 -N N -182 - WO 2004/092166 PCTIUS200-I/010851 o 0 N 0 N 0 ",INH N NNH "'JNH N N r 1I-D - : N0 NN F K'F F F ozz:Sz o / o 0 'NH I N H H IINHNH K iNN IN F F F FF F F N0 o "'INH N NH N .1NH 0~N K i i i - N I - NN H F \N0N F tKN F F N 0 o No N 0 "'tNHXN ",INH XNH I -NN NH 110 I-NN F 0N F F - 183- WO 2004/092166 PCT/US2004/010851 HO F F 0 F N 0 N0 ,N "'NH N N H "INH NN ,>N-N N- N N F F O 0 N 0 N 0 ",IH D N -N" -INH ND N NH N 0N Nj N 0/ i O 0 "N )-~NH "NHH N 67- N N N F F K "F 0/ 0?0 O 0 N "INH >-NH N "'NH N -D N C -N N N 0 q7 0 F NF F F - 184 - WO 2004/092166 PCT/US2004/010851 FEI OH F 0 NN NH O N F NF F M F F N 0 ,NH N 0 NN-F NH(: C N NN N '' FCF F OH H 0 o N N N NHO N "'NH 0N NH NNH /N N N N N F F 3 C\ \ OMe N 0 N 0 "NHH F FN N NH F F N and pharmaceutically acceptable salts and individual stereoisomers thereof. - 185- WO 2004/092166 PCT/US2004/010851

21. A compound of the formula: R 0 N o 3 "NH NH 6 -N N N N wherein the configuration of the C-3 carbon, the configuration of the C-6 carbon, and R' are 5 selected from a single row in the following table: C-3 C-6 R1 R S H R R H R S CH 3 R S CH 2 CH 3 R S CH 2 CF 3 R S CH 2 CO 2 CH 3 R S CH 2 CO 2 H R S (CH 2 ) 2 0CH 2 CH 3 R S CH 2 CN R S (CH 2 ) 2 0H R S >--CH 2 R S CH2 - 186 - WO 2004/092166 PCT/US2004/010851 R S CH 2 CH 2 F R S CH 2 CHF 2 R S CH 2 CHCF 2 R s H R s -H N R S H 2 C--O R S a_~C R s H 2 N OH 2 R S 0 R s__ OH 2 R sQ0 R S (CH 2 ) 2 0CF 3 R s 0 \--~ - 187 - WO 2004/092166 PCT/US2004/010851 R S HO CH 2 R S HO CH 2 R S H 2 N CH R S HO CH 2 F 3 C R S CH2 R S Ph R S 0 N CH 2 and pharmaceutically acceptable salts and individual stereoisomers thereof.

22. A compound of the formula: 5 R, 0 N 0 "NH R2 6- _ND N N 0 N wherein the configuration of the C-6 carbon, and RI and R 2 are selected from a single row in the following table: - 188 - WO 2004/092166 PCT/US2004/010851 C-6 RI R2 RorS H S H RorS H F RorS H F RorS HF F R H F F R or S H RorS H RorS H -189- WO 2004/092166 PCT/US200t1010851 R orS [>-CH 2 HO S >-CH, HOv R >--CH, ~ HN 2 R or S H F R_ orSH F: : RorS H FF RorS H H RorS H ___ H 3 RorS H HC3 -190- WO 2004/092166 PCT/US2004/010851 R brS H S H R or S H R or S H R or S H R or S H S Et S CH 2 CH 2 F - 191 - WO 2004/092166 PCT/US2004/010851 S CH 2 CH 2 OMe RorS Et RorS Me Cl Cl S Me Cl Cl S Et C1 CI RorS Et F Cl R or S CH 2 CF 3 C Cl and pharmaceutically acceptable salts and individual stereoisomers thereof. 5 - 192 - WO 2004/092166 PCT/US2004/010851

23. A compound of the formula: R O N O N N H O N 5 wherein the configuration of the C-3 carbon, the configuration of the C-6 carbon, and RI are selected from a single row in the following table: C-3 C-6 R1 R S CH2 S R CH2 R R CH2 S S __CH2 and pharmaceutically acceptable salts and individual stereoisomers thereof. 10

24. A compound of the formula: N O N N NH F 15 - 193 - WO 2004/092166 PCT/US2004/010851 wherein R is selected from: CH 3 , Ac - N/ L OH 2 .CH 2 CH 2 SO 2 CH 3 , 0H 2 CH 3 , F 3 O O-- H 2 H n'- H 2 N (DN,-,OH 2 , )-H O CH 2 CH 2 F, /N N~~H OH 2 F CH 2 CHFZ, Me U-CH 2 0H 2 00 2 0H(0H 3 ) 2 , 0 2 .~OOHO 2 H H2N,-CH 2 , ~O 2 OH ___ ___ ___ ___ F 3 O O--H 2 , 0 CH2 CO2 CH 3 ,0 A , r. S.F 3 0 OkH 2 , Me__ _ _ _ _ _ _ _ _ _ _ _ _ -194- WO 2004/092166 PCT/US2004/010851 OH N ',CH 2 , '7,CH 2 , HN -No OMe F 3 C H 2 , OH \a SO 2 CH 3 N, CH2,H2C SO 2 CH 3 , Me N CH 2 H 2 C N H 2 C N H 2 , CH 2 H 2 CH 2 F 3 , CH (H 3 ) 2 , OC 2 ____ ___ _CH2__O CH 2 MeO 2 C~H 2 , NII H Me , HO 2 CCH 2 , MCH2 H2, - 195 - WO 2004/092166 PCT/US2004/010851 /Me CH 2 CO 2 H, and N CH 2 , I / CH 2 0 CH 2, and pharmaceutically acceptable salts and individual stereoisomers thereof.

25. A compound of the formula: 5 R % 0 N 0 ".INH % -NH NN F F N wherein R is selected from: OH 3 . CH 2 CH 2 SOCH 3 , CH 2 CH 2 SCH 3 , >- OH 2 CH 2 CH 2 SO 2 CH 3 , CH 2 OHF 2 , CH 2 CH 2 00H 3 ,FC 0 CH 2 CH 2 OCF 3 , and CH 2 CH 2 OH, ________ 10 and pharmaceutically acceptable salts and individual stereoisomners thereof.

26. A compound of the formula: - 196 - WO 2004/092166 PCT/US2004/010851 R1 N O R2 O N NN N wherein the configuration of the C-3 carbon, the configuration of the C-5 carbon, R 1 and R 2 are selected from a single row in the following table: 5 C-3 C-5 R' R 2 R or S R or S CH 2 CH 2 0CH 3 R or S R or S CH 3 R or S R or S CH 3 F F R or S R or S CH 2 CF 3 RorS RorS CH 2 CF 3 ___ F F R R CH 2 CF 3 R S CH 2 CF 3 - 197 - WO 2004/092166 PCT/US2004/010851 S R CH 2 CF 3 S S CH 2 CF 3 and pharmaceutically acceptable salts and individual stereoisomers thereof.

27. A compound of the formula: 5 F 3 C> \ O N N>N N NH R2 O N wherein R 2 is selected from: 10 CH2 H, and 15 and pharmaceutically acceptable salts and individual stereoisomers thereof. 20

28. A pharmaceutical composition which comprises an inert carrier and the compound of Claim 1. - 198 - WO 2004/092166 PCT/US2004/010851

29. The use of the compound of Claim I for the preparation of a medicament useful in the treatment of headache, migraine or cluster headache. - 199-